Anti-bacterial heterocyclic compounds and their synthesis

ABSTRACT

The invention relates to compounds of Formula I and Formula (B) along with their stereoisomers, pharmaceutically acceptable salts, complexes, hydrates, solvates, tautomers, polymorphs, racemic mixtures, optically active forms, and pharmaceutically active derivatives thereof. These compounds are useful for killing or inhibiting the growth of a microorganism selected from the group consisting of bacteria, virus, fungi, and protozoa.

CROSS-REFERENCE TO RELATED APPLICATIONS

-   -   This application is a Section 371 of International Application        No. PCT/IN2018/050799, filed Nov. 29, 2018, which was published        in the English language on Jun. 6, 2019, under International        Publication No. WO 2019/106693 A1, which is incorporated herein        by reference in its entirety, which claims priority under 35        U.S.C. § 119(b) to Indian Application No. 201741042876, filed        Nov. 29, 2017.

FIELD OF THE INVENTION

The present disclosure relates to the field of medicinal chemistry andmore particularly to the synthesis, characterization and development ofbacterial topoisomerase inhibitors effective against Gram-positive andGram-negative bacterial species with a broad spectrum of antibacterialactivity. In particular the present disclosure relates to compounds ofFormula I, their stereoisomers, pharmaceutically acceptable salts,complexes, hydrates, solvates, tautomers, polymorphs, racemic mixtures,optically active forms and pharmaceutically active derivatives thereofand pharmaceutical compositions containing them as active ingredient.

BACKGROUND OF THE INVENTION

Antimicrobial agents are basically the substances that kill or inhibitthe growth of microorganisms. These substances can be derived eitherfrom natural sources or can be prepared synthetically. Due to theirutility in the treatment of infections, antimicrobial agents remain aserious concern for the World Health Organization as they form essentialcomponents of drugs used for human and animal health, and welfare (Bush,K., ASM News, 2004, 70, 282-287).

Despite the efforts to furnish improved antimicrobials in the market,bacteria continue to evolve over these newly developed antimicrobialagents through their efficient resistance mechanism. Resistance to theantimicrobial agents has emerged as a global public health concern inthe past few years. The growing adverse impact on public health,therefore, remains the driving force for the innovation and developmentof new antimicrobial agents.

The world expects to have effective drugs available for every disease,but resistance is a growing menace to this regime and thereforebiologically active compounds exhibiting potent antimicrobial activityneed to be developed. Based on their structural diversity and widespectrum biological activity, heterocyclic compounds could be taken inconsideration as promising compounds that could overcome the resistanceproblems existing with the current antimicrobial agents.

SUMMARY OF THE INVENTION

The present disclosure provides a compound of Formula I

or its stereoisomers, pharmaceutically acceptable salts, complexes,hydrates, solvates, tautomers, polymorphs, racemic mixtures, opticallyactive forms, and pharmaceutically active derivatives thereof, whereinR₁ is selected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₃₋₆ cycloalkyl, C₁₋₆alkylamino, C₁₋₆ aminoalkylene, or 4-7 membered saturated or unsaturatedcarbocyclyl or heterocyclyl ring, wherein the heterocyclyl ring isoptionally substituted with upto three heteroatoms independentlyselected from O, N or S, wherein C₁₋₆ alkyl, C₂₋₆ alkenyl, C₃₋₆cycloalkyl, C₁₋₆ alkylamino, C₁₋₆ aminoalkylene, and 4-7 memberedsaturated or unsaturated carbocyclyl or heterocyclyl ring are optionallysubstituted with 1 to 3 groups independently selected from halogen,amino, hydroxyl, SO₃H, O—PO₃H₂, COOR₉, CONHR₉, SO₂NHR₉, methylsulfone,C₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₆ haloalkoxy, C₃₋₆ cycloalkyl, C₃₋₆cycloalkylamino, C₃₋₆ aminocycloalkyl, C₃₋₆ cycloalkylhydroxy, C₁₋₆alkylamino, or 3-7 membered saturated or unsaturated heterocyclyl ringoptionally substituted with upto three heteroatoms independentlyselected from O, N or S; R₉ is selected from hydrogen, or C₁₋₆ alkyl; R₂is selected from hydrogen, fluorine, chlorine, cyano, C₁₋₆ alkoxy, orhydroxyl; R₃ is selected from hydrogen, C₁₋₆ alkyl, fluorine, C₁₋₆alkoxy, hydroxyl, or amino; X₁ is N or CR₄; R₄ is selected fromhydrogen, halogen, cyano, C₁₋₆ alkoxy, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy,or C₁₋₆ alkyl; X₂ is N or CR₅; R₅ is selected from hydrogen, halogen,cyano, C₁₋₆ alkoxy, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, or C₁₋₆ alkyl; X₃is N or CR₆; and X₄ is CR₆ when dotted line (----) represents a bond; R₆is selected from hydrogen, cyano, C₁₋₆ alkyl, C₁₋₆ alkylamino, C₁₋₆alkoxy, C₁₋₆ haloalkoxy, or COOH; or X₃ is CH₂ or O; and X₄ is CH₂ whendotted line (---) represents no bond; n₁ is 0 to 2; Y₁, and Y₂ areindependently selected from N or CR₇; R₇ is selected from hydrogen,halogen, cyano, C₁₋₆ alkoxy, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, or C₁₋₆alkyl; Z₁ is selected from O, S, NH, or CH₂; and R₈ is selected fromhydrogen, hydroxyl, C₁₋₆ alkyl, or fluorine.

The present disclosure further relates to a compound of Formula I, orits stereoisomers, pharmaceutically acceptable salts, complexes,hydrates, solvates, tautomers, polymorphs, racemic mixtures, opticallyactive forms, and pharmaceutically active derivatives thereof, for usein killing or inhibiting the growth of a microorganism selected from thegroup consisting of bacteria, virus, fungi, and protozoa.

The present disclosure further relates to use of a compound of FormulaI, or its stereoisomers, pharmaceutically acceptable salts, complexes,hydrates, solvates, tautomers, polymorphs, racemic mixtures, opticallyactive forms, and pharmaceutically active derivatives thereof, for usein killing or inhibiting the growth of a microorganism selected from thegroup consisting of bacteria, virus, fungi, and protozoa.

The present disclosure provides a compound of Formula (B)

or its stereoisomers, pharmaceutically acceptable salts, complexes,hydrates, solvates, tautomers, polymorphs, racemic mixtures, opticallyactive forms, and pharmaceutically active derivatives thereof, whereinY₁, and Y₂ are independently selected from N or CR₇; R₇ is selected fromhydrogen, halogen, cyano, C₁₋₆ alkoxy, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy,or C₁₋₆ alkyl; Z₁ is selected from O, S, NH, or CH₂; and R₈ is selectedfrom hydrogen, hydroxyl, C₁₋₆ alkyl, or fluorine.

The present disclosure further relates to a compound of Formula I, orits stereoisomers, pharmaceutically acceptable salts, complexes,hydrates, solvates, tautomers, polymorphs, racemic mixtures, opticallyactive forms, and pharmaceutically active derivatives thereof, for usein treating a disease or condition in a patient, wherein said disease orcondition is caused by a microorganism selected from the groupconsisting of Gram-positive, and Gram-negative pathogens.

The present disclosure further relates to use of a compound of FormulaI, or Formula (B), or its stereoisomers, pharmaceutically acceptablesalts, complexes, hydrates, solvates, tautomers, polymorphs, racemicmixtures, optically active forms, and pharmaceutically activederivatives thereof, in treating a disease or condition in a patient,wherein said disease or condition is caused by a microorganism selectedfrom the group consisting of Gram-positive, and Gram-negative pathogens.The patient is typically a mammal, preferably a human.

The present disclosure further relates to a method of treating abacterial infection or condition in a subject, said method comprisingadministering to a subject a compound of Formula I, or Formula (B), orits stereoisomers, pharmaceutically acceptable salts, complexes,hydrates, solvates, tautomers, polymorphs, racemic mixtures, opticallyactive forms, and pharmaceutically active derivatives thereof, whereinsaid bacterial infection or condition is caused by microorganismselected from the group consisting of Gram-positive, and Gram-negativepathogens.

The present disclosure relates to a pharmaceutical compositioncomprising a compound of Formula I, or Formula (B), or itsstereoisomers, pharmaceutically acceptable salts, complexes, hydrates,solvates, tautomers, polymorphs, racemic mixtures, optically activeforms, and pharmaceutically active derivatives thereof together with apharmaceutically acceptable carrier.

The present disclosure relates to a pharmaceutical compositioncomprising a compound of Formula I, or Formula (B), or itsstereoisomers, pharmaceutically acceptable salts, complexes, hydrates,solvates, tautomers, polymorphs, racemic mixtures, optically activeforms, and pharmaceutically active derivatives thereof together with apharmaceutically acceptable carrier, optionally with one or more otherpharmaceutical compositions.

The present disclosure relates to a pharmaceutical compositioncomprising a compound of Formula I, or Formula (B), or itsstereoisomers, pharmaceutically acceptable salts, complexes, hydrates,solvates, tautomers, polymorphs, racemic mixtures, optically activeforms, and pharmaceutically active derivatives thereof together with apharmaceutically acceptable carrier, and in combination with at leastone antibiotic.

The present disclosure relates to a process of preparation of compoundsof Formula I, or its stereoisomers, pharmaceutically acceptable salts,complexes, hydrates, solvates, tautomers, polymorphs, racemic mixtures,optically active forms, and pharmaceutically active derivatives thereof,said process comprising reacting compounds of Formula (A), and compoundsof Formula (B) in presence of at least one reducing agent, and anadsorbent to obtain the compounds of Formula I.

The present disclosure relates to a process of preparation of acomposition comprising a compound of Formula I, or Formula (B), or itsstereoisomers, pharmaceutically acceptable salts, complexes, hydrates,solvates, tautomers, polymorphs, racemic mixtures, optically activeforms, and pharmaceutically active derivatives thereof, together with apharmaceutically acceptable carrier.

The present disclosure relates to a process of preparation of acomposition comprising a compound of Formula I, or Formula (B), or itsstereoisomers, pharmaceutically acceptable salts, complexes, hydrates,solvates, tautomers, polymorphs, racemic mixtures, optically activeforms, and pharmaceutically active derivatives thereof, together with apharmaceutically acceptable carrier, optionally in combination with oneor more other pharmaceutical compositions.

These and other features, aspects, and advantages of the present subjectmatter will become better understood with reference to the followingdescription. This summary is provided to introduce a selection ofconcepts in a simplified form. This summary is not intended to identifykey features or essential features of the disclosure, nor is it intendedto be used to limit the scope of the subject matter.

DETAILED DESCRIPTION

Those skilled in the art will be aware that the present disclosure issubject to variations and modifications other than those specificallydescribed. It is to be understood that the present disclosure includesall such variations and modifications. The disclosure also includes allsuch steps, features, compositions and compounds referred to orindicated in this specification, individually or collectively, and anyand all combinations of any or more of such steps or features.

Definitions

For convenience, before further description of the present disclosure,certain terms employed in the specification, and examples are collectedhere. These definitions should be read in the light of the remainder ofthe disclosure and understood as by a person of skill in the art. Theterms used herein have the meanings recognized and known to those ofskill in the art, however, for convenience and completeness, particularterms and their meanings are set forth below.

The articles “a”, “an” and “the” are used to refer to one or to morethan one (i.e., to at least one) of the grammatical object of thearticle.

Throughout the description and the claims which follow, unless thecontext requires otherwise, the word “comprise”, and variations such as“comprises” and “comprising”, will be understood to imply the inclusionof a stated integer or step or group of integers but not to theexclusion of any other integer or step or group of integers or steps.

The term “including” is used to mean “including but not limited to”.“Including” and “including but not limited to” are used interchangeably.

In the structural formulae given herein and throughout the presentdisclosure, the following terms have been indicated meaning, unlessspecifically stated otherwise.

In this specification, the prefix C_(x-y) as used in terms such asC_(x-y) alkyl, and the like (where x and y are integers) indicates thenumerical range of carbon atoms that are present in the group; forexample, C₁₋₆ alkyl includes C₁ alkyl (methyl), C₂ alkyl (ethyl), C₃alkyl (propyl and isopropyl), and C₄ alkyl (butyl, 1-methylpropyl,2-methylpropyl, and t-butyl). Unless specifically stated, the bondingatom of a group may be any suitable atom of that group; for example,propyl includes prop-1-yl, and prop-2-yl.

The term “alkyl” refers to a monoradical branched or unbranchedsaturated hydrocarbon chain having from 1 to 6 carbon atoms. This termis exemplified by groups such as n-butyl, iso-butyl, t-butyl, n-hexyl,n-decyl, and the like. The groups may be optionally substituted.

The term “haloalkyl” as used herein refers to an alkyl group in whichone or more hydrogen atoms are replaced by the same number of identicalor different halogen atoms. The term “haloalkyl” is exemplified bygroups such as chloromethyl, trifluoromethyl, 1-fluoroethyl,2,2,2-trifluoroethyl, and the like.

The term “alkylene” refers to a diradical branched or unbranchedsaturated hydrocarbon chain having from 1 to 6 carbon atoms. This termis exemplified by groups such as methylene, ethylene, propylene,butylene, hexylene, and the like. The groups may be optionallysubstituted. Representative substituted alkylene groups include hydroxylsubstituted alkylenes, amino substituted alkylene.

The term “alkenyl” refers to a monoradical of a branched or unbranchedunsaturated hydrocarbon group preferably having from 2, 3, 4, 5, or 6carbon atoms, and having 1, 2, or 3, double bond (vinyl), preferably 1double bond. The groups may be optionally substituted.

The term “cycloalkyl” or “carbocyclyl” refers to carbocyclic groups offrom 3 to 6 carbon atoms having a single cyclic ring or multiplecondensed rings which may be partially unsaturated. Such cycloalkylgroups include, by way of example, single ring structures such ascyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl,cyclohexenyl, and the like, or multiple ring structures or carbocyclicgroups to which is fused an aryl group, for example indane, and thelike. The groups may be optionally substituted.

The terms “alkoxyl” or “alkoxy” refers to an alkyl group, as definedabove, having an oxygen radical attached thereto. Representative alkoxylgroups include methoxy, ethoxy, propyloxy, tert-butoxy, and the like. An“ether” is two hydrocarbons covalently linked by an oxygen. Accordingly,the substituent of an alkyl that renders that alkyl an ether is orresembles an alkoxyl, such as can be represented by one of —O-alkyl,—O-alkenyl, —O-alkynyl.

“Halo” or “Halogen”, alone or in combination with any other term meanshalogens such as chloro or chlorine (Cl), fluoro or fluorine (F), bromoor bromine (Br), and iodo or iodine (I).

The term “heterocyclyl” refers to a heterocyclic ring radical which maybe optionally substituted by one or more substituents as describedhereinafter in the disclosure. The heterocyclyl ring radical may beattached to the main structure at any heteroatom or carbon atom thatresults in the creation of a stable structure. Furthermore, the term“heterocyclyl” refers to a stable 3 to 7 membered rings radical, whichconsists of carbon atoms and from one to five heteroatoms selected fromnitrogen, phosphorus, oxygen and sulfur. For purposes of this disclosurethe heterocyclic ring radical may be monocyclic, bicyclic or tricyclicring systems, and the nitrogen, phosphorus, carbon, oxygen or sulfuratoms in the heterocyclic ring radical may be optionally oxidized tovarious oxidation states. In addition, the nitrogen atom may beoptionally quaternized; and the ring radical may be partially or fullysaturated. Preferred heterocyclyl groups include, without limitation,azetidinyl, acridinyl, benzodioxolyl, benzodioxanyl, benzofuranyl,carbazolyl, cinnolinyl, dioxolanyl, indolizinyl, naphthyridinyl,perhydroazepinyl, phenazinyl, phenothiazinyl, phenoxazinyl,phthalazinyl, pyridyl, pteridinyl, purinyl, quinazolinyl, qunioxalinyl,quinolinyl, isoquinolinyl, tetrazolyl, imidazolyl,tetrahydroisoquinolinyl, piperidinyl, piperazinyl, homopiperazinyl,2-oxoazepinyl, azepinyl, pyrrolyl, 4-piperidonyl, pyrrolidinyl,pyrazinyl, pyrimidinyl, pyridazinyl, oxazolyl, oxazolinyl, triazolyl,indanyl, isoxazolyl, isoxazolidinyl, thiazolyl, thiazolinyl,thiazolidinyl, isothiazolyl, quinuclidinyl, isothiazolidinyl, indolyl,isoindolyl, indolinyl, isoindolinyl, octahydroindolyl,octahydroisoindolyl, quinolyl, isoquinolyl, decahydroisoquinolyl,benzimidazolyl, thiadiazolyl, benzopyranyl, benzothiazolyl,benzooxazolyl, thienyl, morpholinyl, thiomorpholinyl,thiamorpholinylsulfoxide, furyl, tetrahydrofuryl, tetrahydropyranyl,chromanyl and isochromanyl.

As used herein, the term “substituted” is contemplated to include allpermissible substituents of organic compounds. In a broad aspect, thepermissible substituents include acyclic and cyclic, branched andunbranched, carbocyclic and heterocyclic, aromatic and nonaromaticsubstituents of organic compounds. Illustrative substituents include,for example, those described herein above. The permissible substituentscan be one or more and the same or different for appropriate organiccompounds. For purposes of this disclosure, the heteroatoms such asnitrogen may have hydrogen substituent, and/or any permissiblesubstituents of organic compounds described herein which satisfy thevalences of the heteroatoms.

The term “effective amount” means an amount of a compound or compositionwhich is sufficient enough to significantly and positively modify thesymptoms and/or conditions to be treated (e.g., provide a positiveclinical response). The effective amount of an active ingredient for usein a pharmaceutical composition will vary with the particular conditionbeing treated, the severity of the condition, the duration of thetreatment, the nature of concurrent therapy, the particular activeingredient(s) being employed, the particular pharmaceutically-acceptableexcipient(s)/carrier(s) utilized, the route of administration, and likefactors within the knowledge and expertise of the attending physician.

The compounds described herein may contain one or more chiral centersand/or double bonds and therefore, may exist as stereoisomers, such asdouble-bond isomers (i.e., geometric isomers), regioisomers, enantiomersor diastereomers. Accordingly, the chemical structures depicted hereinencompass all possible enantiomers and stereoisomers of the illustratedor identified compounds including the stereoisomerically pure form(e.g., geometrically pure, enantiomerically pure or diastereomericallypure) and enantiomeric and stereoisomeric mixtures. Enantiomeric andstereoisomeric mixtures can be resolved into their component enantiomersor stereoisomers using separation techniques or chiral synthesistechniques well known to the person skilled in the art. The compoundsmay also exist in several tautomeric forms including the enol form, theketo form, and mixtures thereof. Accordingly, the chemical structuresdepicted herein encompass all possible tautomeric forms of theillustrated or identified compounds.

The term “pharmaceutically acceptable” refers to those compounds,materials, compositions, and/or dosage forms which are, within the scopeof sound medical judgment, suitable for use in contact with the tissuesof human beings and animals without excessive toxicity, irritation,allergic response, or other problem or complication, commensurate with areasonable benefit/risk ratio.

“Pharmaceutically acceptable salt” embraces salts with apharmaceutically acceptable acid or base. Pharmaceutically acceptableacids include both inorganic acids, for example hydrochloric, sulphuric,phosphoric, diphosphoric, hydrobromic, hydroiodic, and nitric acid andorganic acids, for example citric, fumaric, maleic, malic, mandelic,ascorbic, oxalic, succinic, tartaric, benzoic, acetic, methanesulphonic,ethanesulphonic, benzenesulphonic or p-toluenesulphonic acid.Pharmaceutically acceptable bases include alkali metal (e.g. sodium orpotassium) and alkali earth metal (e.g. calcium or magnesium)hydroxides, and organic bases, for example alkyl amines, arylalkylamines and heterocyclic amines.

The compounds discussed herein in many instances may have been namedand/or checked with ACD/Name by ACD/Labs® and/or Chemdraw byCambridgeSoft®.

The term “polymorphs” refers to crystal forms of the same molecule, anddifferent polymorphs may have different physical properties such as, forexample, melting temperatures, heats of fusion, solubilities,dissolution rates and/or vibrational spectra as a result of thearrangement or conformation of the molecules in the crystal lattice.

The term “solvate”, as used herein, refers to a crystal form of asubstance which contains solvent.

The term “hydrate” refers to a solvate wherein the solvent is water.

As discussed in the background section, the effective resistancemechanisms of the microbes (especially bacteria) pose a serious threatto human health. Therefore, new and efficient antimicrobial(antibacterial) agents need to be developed as a measure against theadversaries posed on human health globally by microbes. The presentdisclosure provides compounds that can act as efficient antibacterialagents combating both the resistant and non-resistant strains.

According to an embodiment, the present disclosure relates to a compoundof Formula I

or its stereoisomers, pharmaceutically acceptable salts, complexes,hydrates, solvates, tautomers, polymorphs, racemic mixtures, opticallyactive forms, and pharmaceutically active derivatives thereof, whereinR₁ is selected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₃₋₆ cycloalkyl, C₁₋₆alkylamino, C₁₋₆ aminoalkylene, or 4-7 membered saturated or unsaturatedcarbocyclyl or heterocyclyl ring, wherein the heterocyclyl ring isoptionally substituted with upto three heteroatoms independentlyselected from O, N or S, wherein C₁₋₆ alkyl, C₂₋₆ alkenyl, C₃₋₆cycloalkyl, C₁₋₆ alkylamino, C₁₋₆ aminoalkylene, and 4-7 memberedsaturated or unsaturated carbocyclyl or heterocyclyl ring are optionallysubstituted with 1 to 3 groups independently selected from halogen,amino, hydroxyl, SO₃H, O—PO₃H₂, COOR₉, CONHR₉, SO₂NHR₉, methylsulfone,C₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₆ haloalkoxy, C₃₋₆ cycloalkyl, C₃₋₆cycloalkylamino, C₃₋₆ aminocycloalkyl, C₃₋₆ cycloalkylhydroxy, C₁₋₆alkylamino, or 3-7 membered saturated or unsaturated heterocyclyl ringoptionally substituted with upto three heteroatoms independentlyselected from O, N or S; R₉ is selected from hydrogen, or C₁₋₆ alkyl; R₂is selected from hydrogen, fluorine, chlorine, cyano, C₁₋₆ alkoxy, orhydroxyl; R₃ is selected from hydrogen, C₁₋₆ alkyl, fluorine, C₁₋₆alkoxy, hydroxyl, or amino; X₁ is N or CR₄; R₄ is selected fromhydrogen, halogen, cyano, C₁₋₆ alkoxy, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy,or C₁₋₆ alkyl; X₂ is N or CR₅; R₅ is selected from hydrogen, halogen,cyano, C₁₋₆ alkoxy, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, or C₁₋₆ alkyl; X₃is N or CR₆; and X₄ is CR₆ when dotted line (----) represents a bond; R₆is selected from hydrogen, cyano, C₁₋₆ alkyl, C₁₋₆ alkylamino, C₁₋₆alkoxy, C₁₋₆ haloalkoxy, or COOH; or X₃ is CH₂ or O; and X₄ is CH₂ whendotted line (----) represents no bond; n₁ is 0 to 2; Y₁, and Y₂ areindependently selected from N or CR₇; R₇ is selected from hydrogen,halogen, cyano, C₁₋₆ alkoxy, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, or C₁₋₆alkyl; Z₁ is selected from O, S, NH, or CH₂; and R₈ is selected fromhydrogen, hydroxyl, C₁₋₆ alkyl, or fluorine.

According to an embodiment, the present disclosure relates to a compoundof Formula I or its stereoisomers, pharmaceutically acceptable salts,complexes, hydrates, solvates, tautomers, polymorphs, racemic mixtures,optically active forms and pharmaceutically active derivatives thereof,wherein R₁ is selected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₃₋₆ cycloalkyl,C₁₋₆ alkylamino, C₁₋₆ aminoalkylene, or 4-7 membered saturated orunsaturated carbocyclyl or heterocyclyl ring, wherein the heterocyclylring is optionally substituted with upto three heteroatoms independentlyselected from O, N or S, wherein C₁₋₆ alkyl, C₂₋₆ alkenyl, C₃₋₆cycloalkyl, C₁₋₆ alkylamino, C₁₋₆ aminoalkylene, and 4-7 memberedsaturated or unsaturated carbocyclyl or heterocyclyl ring are optionallysubstituted with 1 to 3 groups independently selected from halogen,amino, hydroxyl, SO₃H, O—PO₃H₂, COOR₉, CONHR₉, SO₂NHR₉, methylsulfone,C₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₆ haloalkoxy, C₃₋₆ cycloalkyl, C₃₋₆cycloalkylamino, C₃₋₆ aminocycloalkyl, C₃₋₆ cycloalkylhydroxy, C₁₋₆alkylamino, or 3-7 membered saturated or unsaturated heterocyclyl ringoptionally substituted with upto three heteroatoms independentlyselected from O, N or S; R₉ is selected from hydrogen, or C₁₋₆ alkyl; R₂is selected from hydrogen, fluorine, chlorine, cyano, C₁₋₅ alkoxy, orhydroxyl; R₃ is selected from hydrogen, C₁₋₅ alkyl, fluorine, C₁₋₅alkoxy, hydroxyl, or amino; X₁ is N or CR₄; R₄ is selected fromhydrogen, halogen, cyano, C₁₋₅ alkoxy, C₁₋₅ haloalkyl, C₁₋₅ haloalkoxy,or C₁₋₅ alkyl; X₂ is N or CR₅; R₅ is selected from hydrogen, halogen,cyano, C₁₋₅ alkoxy, C₁₋₅ haloalkyl, C₁₋₅ haloalkoxy, or C₁₋₅ alkyl; X₃is N or CR₆; and X₄ is CR₆ when dotted line (----) represents a bond; R₆is selected from hydrogen, cyano, C₁₋₅ alkyl, C₁₋₅ alkylamino, C₁₋₅alkoxy, C₁₋₅ haloalkoxy, or COOH; or X₃ is CH₂ or O; and X₄ is CH₂ whendotted line (----) represents no bond; n₁ is 0 to 2; Y₁, and Y₂ areindependently selected from N or CR₇; R₇ is selected from hydrogen,halogen, cyano, C₁₋₅ alkoxy, C₁₋₅ haloalkyl, C₁₋₅ haloalkoxy, or C₁₋₅alkyl; Z₁ is selected from O, S, NH, and CH₂; or R₈ is selected fromhydrogen, hydroxyl, C₁₋₆ alkyl, or fluorine.

According to an embodiment, the present disclosure relates to a compoundof Formula I or its stereoisomers, pharmaceutically acceptable salts,complexes, hydrates, solvates, tautomers, polymorphs, racemic mixtures,optically active forms and pharmaceutically active derivatives thereof,wherein R₁ is selected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₃₋₆ cycloalkyl,C₁₋₆ alkylamino, C₁₋₆ aminoalkylene, or 4-7 membered saturated orunsaturated carbocyclyl or heterocyclyl ring, wherein the heterocyclylring is optionally substituted with upto three heteroatoms independentlyselected from O, N or S, wherein C₁₋₆ alkyl, C₂₋₆ alkenyl, C₃₋₆cycloalkyl, C₁₋₆ alkylamino, C₁₋₆ aminoalkylene, and 4-7 memberedsaturated or unsaturated carbocyclyl or heterocyclyl ring are optionallysubstituted with 1 to 3 groups independently selected from halogen,amino, hydroxyl, SO₃H, O—PO₃H₂, COOR₉, CONHR₉, SO₂NHR₉, methylsulfone,C₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₆ haloalkoxy, C₃₋₆ cycloalkyl, C₃₋₆cycloalkylamino, C₃₋₆ aminocycloalkyl, C₃₋₆ cycloalkylhydroxy, C₁₋₆alkylamino, or 3-7 membered saturated or unsaturated heterocyclyl ringoptionally substituted with upto three heteroatoms independentlyselected from O, N or S; R₉ is selected from hydrogen, or C₁₋₆ alkyl; R₂is selected from hydrogen, fluorine, chlorine, cyano, C₁₋₅ alkoxy, orhydroxyl; R₃ is selected from hydrogen, C₁₋₅ alkyl, fluorine, C₁₋₆alkoxy, hydroxyl, or amino; X₁ is N or CR₄; R₄ is selected fromhydrogen, halogen, cyano, C₁₋₅ alkoxy, C₁₋₅ haloalkyl, C₁₋₅ haloalkoxy,or C₁₋₅ alkyl; X₂ is N; X₃ is N or CR₆; and X₄ is CR₆ when dotted line(----) represents a bond; R₆ is selected from hydrogen, cyano, C₁₋₅alkyl, C₁₋₅ alkylamino, C₁₋₅ alkoxy, C₁₋₅ haloalkoxy, or COOH; or X₃ isCH₂ or O; and X₄ is CH₂ when dotted line (----) represents no bond; n₁is 0 to 2; Y₁, and Y₂ are independently selected from N or CR₇; R₇ isselected from hydrogen, halogen, cyano, C₁₋₅ alkoxy, C₁₋₅ haloalkyl,C₁₋₅ haloalkoxy, or C₁₋₅ alkyl; Z₁ is selected from O, S, NH, or CH₂;and R₈ is selected from hydrogen, hydroxyl, C₁₋₆ alkyl, or fluorine.

According to an embodiment, the present disclosure relates to a compoundof Formula I or its stereoisomers, pharmaceutically acceptable salts,complexes, hydrates, solvates, tautomers, polymorphs, racemic mixtures,optically active forms and pharmaceutically active derivatives thereof,wherein R₁ is selected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₃₋₆ cycloalkyl,C₁₋₆ alkylamino, C₁₋₆ aminoalkylene, or 4-7 membered saturated orunsaturated carbocyclyl or heterocyclyl ring, wherein the heterocyclylring is optionally substituted with upto three heteroatoms independentlyselected from O, N or S, wherein C₁₋₆ alkyl, C₂₋₆ alkenyl, C₃₋₆cycloalkyl, C₁₋₆ alkylamino, C₁₋₆ aminoalkylene, and 4-7 memberedsaturated or unsaturated carbocyclyl or heterocyclyl ring are optionallysubstituted with 1 to 3 groups independently selected from halogen,amino, hydroxyl, SO₃H, O—PO₃H₂, COOR₉, CONHR₉, SO₂NHR₉, methylsulfone,C₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₆ haloalkoxy, C₃₋₆ cycloalkyl, C₃₋₆cycloalkylamino, C₃₋₆ aminocycloalkyl, C₃₋₆ cycloalkylhydroxy, C₁₋₆alkylamino, or 3-7 membered saturated or unsaturated heterocyclyl ringoptionally substituted with upto three heteroatoms independentlyselected from O, N or S; R₉ is selected from hydrogen, or C₁₋₆ alkyl; R₂is selected from hydrogen, fluorine, chlorine, cyano, C₁₋₅ alkoxy, orhydroxyl; R₃ is selected from hydrogen, C₁₋₅ alkyl, fluorine, C₁₋₆alkoxy, hydroxyl, or amino; X₁ is N or CR₄; R₄ is selected fromhydrogen, halogen, cyano, C₁₋₅ alkoxy, C₁₋₅ haloalkyl, C₁₋₅ haloalkoxy,or C₁₋₅ alkyl; X₂ is CR₅; R₅ is selected from hydrogen, halogen, cyano,or C₁₋₅ alkyl; X₃ is N or CR₆; and X₄ is CR₆ when dotted line (----)represents a bond; R₆ is selected from hydrogen, cyano, C₁₋₅ alkyl, C₁₋₅alkylamino, C₁₋₅ alkoxy, C₁₋₅ haloalkoxy, or COOH; or X₃ is CH₂ or O;and X₄ is CH₂ when dotted line (----) represents no bond; n₁ is 0 to 2;Y₁, and Y₂ are independently selected from N or CR₇; R₇ is selected fromhydrogen, halogen, cyano, C₁₋₅ alkoxy, C₁₋₅ haloalkyl, C₁₋₅ haloalkoxy,or C₁₋₅ alkyl; Z₁ is selected from O, S, NH, or CH₂; and R₈ is selectedfrom hydrogen, hydroxyl, C₁₋₆ alkyl, or fluorine.

According to an embodiment, the present disclosure relates to a compoundof Formula I or its stereoisomers, pharmaceutically acceptable salts,complexes, hydrates, solvates, tautomers, polymorphs, racemic mixtures,optically active forms and pharmaceutically active derivatives thereof,wherein R₁ is selected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₃₋₆ cycloalkyl,C₁₋₆ alkylamino, C₁₋₆ aminoalkylene, or 4-7 membered saturated orunsaturated carbocyclyl or heterocyclyl ring, wherein the heterocyclylring is optionally substituted with upto three heteroatoms independentlyselected from O, N or S, wherein C₁₋₆ alkyl, C₂₋₆ alkenyl, C₃₋₆cycloalkyl, C₁₋₆ alkylamino, C₁₋₆ aminoalkylene, and 4-7 memberedsaturated or unsaturated carbocyclyl or heterocyclyl ring are optionallysubstituted with 1 to 3 groups independently selected from halogen,amino, hydroxyl, SO₃H, O—PO₃H₂, COOR₉, CONHR₉, SO₂NHR₉, methylsulfone,C₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₆ haloalkoxy, C₃₋₆ cycloalkyl, C₃₋₆cycloalkylamino, C₃₋₆ aminocycloalkyl, C₃₋₆ cycloalkylhydroxy, or 3-7membered saturated or unsaturated heterocyclyl ring optionallysubstituted with upto three heteroatoms independently selected from O, Nor S; R₉ is selected from hydrogen, or C₁₋₆ alkyl; R₂ is selected fromhydrogen, fluorine, chlorine, cyano, C₁₋₅ alkoxy, or hydroxyl; R₃ isselected from hydrogen, C₁₋₅ alkyl, fluorine, C₁₋₆ alkoxy, hydroxyl, oramino; X₁ is N or CR₄; R₄ is selected from hydrogen, halogen, cyano,C₁₋₅ alkoxy, C₁₋₅ haloalkyl, C₁₋₅ haloalkoxy, or C₁₋₅ alkyl; X₂ is N orCR₅; R₅ is selected from hydrogen, halogen, cyano, C₁₋₅ alkoxy, C₁₋₅haloalkyl, C₁₋₅ haloalkoxy, or C₁₋₅ alkyl; X₃ is N or CR₆; and X₄ is CR₆when dotted line (----) represents a bond; R₆ is selected from hydrogen,cyano, C₁₋₅ alkyl, C₁₋₅ alkylamino, C₁₋₅ alkoxy, C₁₋₅ haloalkoxy, orCOOH; or X₃ is CH₂ or O; and X₄ is CH₂ when dotted line (----)represents no bond; n₁ is 0 to 2; Y₁ is selected from N or CR₇; Y₂ is N;R₇ is selected from hydrogen, halogen, cyano, C₁₋₅ alkoxy, C₁₋₅haloalkyl, C ₁₋₅ haloalkoxy, or C₁₋₅ alkyl; Z₁ is selected from O, S,NH, and CH₂; or R₈ is selected from hydrogen, hydroxyl, C₁₋₆ alkyl, orfluorine.

According to an embodiment, the present disclosure relates to a compoundof Formula I or its stereoisomers, pharmaceutically acceptable salts,complexes, hydrates, solvates, tautomers, polymorphs, racemic mixtures,optically active forms and pharmaceutically active derivatives thereof,wherein R₁ is selected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₃₋₆ cycloalkyl,C₁₋₆ alkylamino, C₁₋₆ aminoalkylene, or 4-7 membered saturated orunsaturated carbocyclyl or heterocyclyl ring, wherein the heterocyclylring is optionally substituted with upto three heteroatoms independentlyselected from O, N or S, wherein C₁₋₆ alkyl, C₂₋₆ alkenyl, C₃₋₆cycloalkyl, C₁₋₆ alkylamino, C₁₋₆ aminoalkylene, and 4-7 memberedsaturated or unsaturated carbocyclyl or heterocyclyl ring are optionallysubstituted with 1 to 3 groups independently selected from halogen,amino, hydroxyl, SO₃H, O—PO₃H₂, COOR₉, CONHR₉, SO₂NHR₉, methylsulfone,C₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₆ haloalkoxy, C₃₋₆ cycloalkyl, C₃₋₆cycloalkylamino, C₃₋₆ aminocycloalkyl, C₃₋₆ cycloalkylhydroxy, C₁₋₆alkylamino, or 3-7 membered saturated or unsaturated heterocyclyl ringoptionally substituted with upto three heteroatoms independentlyselected from O, N or S; R₉ is selected from hydrogen, or C₁₋₆ alkyl; R₂is selected from hydrogen, chlorine, fluorine, cyano, C₁₋₅ alkoxy, orhydroxyl; R₃ is selected from hydrogen, C₁₋₅ alkyl, fluorine, C₁₋₆alkoxy, hydroxyl, or amino; X₁ is N or CR₄; R₄ is selected fromhydrogen, halogen, cyano, C₁₋₅ alkoxy, C₁₋₅ haloalkyl, C₁₋₅ haloalkoxy,or C₁₋₅ alkyl; X₂ is N or CR₅; R₅ is selected from hydrogen, halogen,cyano, C₁₋₅ alkoxy, C₁₋₅ haloalkyl, C₁₋₅ haloalkoxy, or C₁₋₅ alkyl; X₃is N or CR₆; and X₄ is CR₆ when dotted line (----) represents a bond; R₆is selected from hydrogen, cyano, C₁₋₅ alkyl, C₁₋₅ alkylamino, C₁₋₅alkoxy, C₁₋₅ haloalkoxy, or COOH; or X₃ is CH₂ or O; and X₄ is CH₂ whendotted line (----) represents no bond; n₁ is 0 to 2; Y₁ is selected fromN or CR₇; Y₂ is CR₇; R₇ is selected from hydrogen, halogen, cyano, C₁₋₅alkoxy, C₁₋₅ haloalkyl, C₁₋₅ haloalkoxy, or C₁₋₅ alkyl; Z₁ is selectedfrom O, S, NH, or CH₂; and R₈ is selected from hydrogen, hydroxyl, C₁₋₆alkyl, or fluorine.

According to an embodiment, the present disclosure relates to a compoundof Formula I or its stereoisomers, pharmaceutically acceptable salts,complexes, hydrates, solvates, tautomers, polymorphs, racemic mixtures,optically active forms and pharmaceutically active derivatives thereof,wherein R₁ is C₁₋₆ alkyl; R₂ is selected from hydrogen, fluorine,chlorine, cyano, C₁₋₅ alkoxy, or hydroxyl; R₃ is selected from hydrogen,C₁₋₅ alkyl, fluorine, C₁₋₆ alkoxy, hydroxyl, or amino; X₁ is N or CR₄;R₄ is selected from hydrogen, halogen, cyano, C₁₋₅ alkoxy, C₁₋₅haloalkyl, C₁₋₅ haloalkoxy, or C₁₋₅ alkyl; X₂ is N or CR₅; R₅ isselected from hydrogen, halogen, cyano, C₁₋₅ alkoxy, C₁₋₅ haloalkyl,C₁₋₅ haloalkoxy, or C₁₋₅ alkyl; X₃ is N or CR₆; and X₄ is CR₆ whendotted line (----) represents a bond; R₆ is selected from hydrogen,cyano, C₁₋₅ alkyl, C₁₋₅ alkylamino, C₁₋₅ alkoxy, C₁₋₅ haloalkoxy, orCOOH; or X₃ is CH₂ or O; and X₄ is CH₂ when dotted line (----)represents no bond; n₁ is 0 to 2; Y₁, and Y₂ are independently selectedfrom N or CR₇; R₇ is selected from hydrogen, halogen, cyano, C₁₋₅alkoxy, C₁₋₅ haloalkyl, C₁₋₅ haloalkoxy, or C₁₋₅ alkyl; Z₁ is selectedfrom O, S, NH, or CH₂; and R₈ is selected from hydrogen, hydroxyl, C₁₋₆alkyl, or fluorine.

According to an embodiment, the present disclosure relates to a compoundof Formula I or its stereoisomers, pharmaceutically acceptable salts,complexes, hydrates, solvates, tautomers, polymorphs, racemic mixtures,optically active forms and pharmaceutically active derivatives thereof,wherein R₁ is C₁₋₆ alkyl, wherein C₁₋₆ alkyl is further substituted with1 to 3 groups independently selected from halogen, amino, or hydroxyl;R₂ is selected from hydrogen, fluorine, chlorine, cyano, C₁₋₅ alkoxy, orhydroxyl; R₃ is selected from hydrogen, C₁₋₅ alkyl, fluorine, C₁₋₆alkoxy, hydroxyl, or amino; X₁ is N or CR₄; R₄ is selected fromhydrogen, halogen, cyano, C₁₋₅ alkoxy, C₁₋₅ haloalkyl, C₁₋₅ haloalkoxy,or C₁₋₅ alkyl; X₂ is N or CR₅; R₅ is selected from hydrogen, halogen,cyano, C₁₋₅ alkoxy, C₁₋₅ haloalkyl, C₁₋₅ haloalkoxy, or C₁₋₅ alkyl; X₃is N or CR₆; and X₄ is CR₆ when dotted line (----) represents a bond; R₆is selected from hydrogen, cyano, C₁₋₅ alkyl, C₁₋₅ alkylamino, C₁₋₅alkoxy, C₁₋₅ haloalkoxy, or COOH; or X₃ is CH₂ or O; and X₄ is CH₂ whendotted line (----) represents no bond; n₁ is 0 to 2; Y₁, and Y₂ areindependently selected from N or CR₇; R₇ is selected from hydrogen,halogen, cyano, C₁₋₅ alkoxy, C₁₋₅ haloalkyl, C₁₋₅ haloalkoxy, or C₁₋₅alkyl; Z₁ is selected from O, S, NH, or CH₂; and R₈ is selected fromhydrogen, hydroxyl, C₁₋₆ alkyl, or fluorine.

According to an embodiment, the present disclosure relates to a compoundof Formula I or its stereoisomers, pharmaceutically acceptable salts,complexes, hydrates, solvates, tautomers, polymorphs, racemic mixtures,optically active forms and pharmaceutically active derivatives thereof,wherein R₁ is selected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₃₋₆ cycloalkyl,C₁₋₆ alkylamino, C₁₋₆ aminoalkylene, and 4-7 membered saturated orunsaturated carbocyclyl or heterocyclyl ring, wherein the heterocyclylring is optionally substituted with upto three heteroatoms independentlyselected from O, N or S, wherein C₁₋₆ alkyl, C₂₋₆ alkenyl, C₃₋₆cycloalkyl, C₁₋₆ alkylamino, C₁₋₆ aminoalkylene, or 4-7 memberedsaturated or unsaturated carbocyclyl or heterocyclyl ring are optionallysubstituted with 1 to 3 groups independently selected from halogen,amino, hydroxyl, SO₃H, O—PO₃H₂, COOR₉, CONHR₉, SO₂NHR₉, methylsulfone,C₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₆ haloalkoxy, C₃₋₆ cycloalkyl, C₃₋₆cycloalkylamino, C₃₋₆ aminocycloalkyl, C₃₋₆ cycloalkylhydroxy, C₁₋₆alkylamino, or 3-7 membered saturated or unsaturated heterocyclyl ringoptionally substituted with upto three heteroatoms independentlyselected from O, N or S; R₉ is selected from hydrogen, or C₁₋₆ alkyl; R₂is hydrogen; R₃ is selected from hydrogen, C₁₋₅ alkyl, fluorine, C₁₋₆alkoxy, hydroxyl, or amino; X₁ is N or CR₄; R₄ is selected fromhydrogen, halogen, cyano, C₁₋₅ alkoxy, C₁₋₅ haloalkyl, C₁₋₅ haloalkoxy,or C₁₋₅ alkyl; X₂ is N or CR₅; R₅ is selected from hydrogen, halogen,cyano, C₁₋₅ alkoxy, C₁₋₅ haloalkyl, C₁₋₅ haloalkoxy, or C₁₋₅ alkyl; X₃is N or CR₆; and X₄ is CR₆ when dotted line (----) represents a bond; R₆is selected from hydrogen, cyano, C₁₋₅ alkyl, C₁₋₅ alkylamino, C₁₋₅alkoxy, C₁₋₅ haloalkoxy, or COOH; or X₃ is CH₂ or O; and X₄ is CH₂ whendotted line (----) represents no bond; n₁ is 0 to 2; Y₁, and Y₂ areindependently selected from N or CR₇; R₇ is selected from hydrogen,halogen, cyano, C₁₋₅ alkoxy, C₁₋₅ haloalkyl, C₁₋₅ haloalkoxy, or C₁₋₅alkyl; Z₁ is selected from O, S, NH, or CH₂; and R₈ is selected fromhydrogen, hydroxyl, C₁₋₆ alkyl, or fluorine.

According to an embodiment, the present disclosure relates to a compoundof Formula I or its stereoisomers, pharmaceutically acceptable salts,complexes, hydrates, solvates, tautomers, polymorphs, racemic mixtures,optically active forms and pharmaceutically active derivatives thereof,wherein R₁ is selected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₃₋₆ cycloalkyl,C₁₋₆ alkylamino, C₁₋₆ aminoalkylene, or 4-7 membered saturated orunsaturated carbocyclyl or heterocyclyl ring, wherein the heterocyclylring is optionally substituted with upto three heteroatoms independentlyselected from O, N or S, wherein C₁₋₆ alkyl, C₂₋₆ alkenyl, C₃₋₆cycloalkyl, C₁₋₆ alkylamino, C₁₋₆ aminoalkylene, and 4-7 memberedsaturated or unsaturated carbocyclyl or heterocyclyl ring are optionallysubstituted with 1 to 3 groups independently selected from halogen,amino, hydroxyl, SO₃H, O—PO₃H₂, COOR₉, CONHR₉, SO₂NHR₉, methylsulfone,C₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₆ haloalkoxy, C₃₋₆ cycloalkyl, C₃₋₆cycloalkylamino, C₃₋₆ aminocycloalkyl, C₃₋₆ cycloalkylhydroxy, C₁₋₆alkylamino, or 3-7 membered saturated or unsaturated heterocyclyl ringoptionally substituted with upto three heteroatoms independentlyselected from O, N or S; R₉ is selected from hydrogen, or C₁₋₆ alkyl; R₂is fluorine; R₃ is selected from hydrogen, C₁₋₅ alkyl, fluorine, C₁₋₆alkoxy, hydroxyl, or amino; X₁ is N or CR₄; R₄ is selected fromhydrogen, halogen, cyano, C₁₋₅ alkoxy, C₁₋₅ haloalkyl, C₁₋₅ haloalkoxy,or C₁₋₅ alkyl; X₂ is N or CR₅; R₅ is selected from hydrogen, halogen,cyano, C₁₋₅ alkoxy, C₁₋₅ haloalkyl, C₁₋₅ haloalkoxy, or C₁₋₅ alkyl; X₃is N or CR₆; and X₄ is CR₆ when dotted line (----) represents a bond; R₆is selected from hydrogen, cyano, C₁₋₅ alkyl, C₁₋₅ alkylamino, C₁₋₅alkoxy, C₁₋₅ haloalkoxy, or COOH; or X₃ is CH₂ or O; and X₄ is CH₂ whendotted line (----) represents no bond; n₁ is 0 to 2; Y₁, and Y₂ areindependently selected from N or CR₇; R₇ is selected from hydrogen,halogen, cyano, C₁₋₅ alkoxy, C₁₋₅ haloalkyl, C₁₋₅ haloalkoxy, or C₁₋₅alkyl; Z₁ is selected from O, S, NH, or CH₂; and R₈ is selected fromhydrogen, hydroxyl, C₁₋₆ alkyl, or fluorine.

According to an embodiment, the present disclosure relates to a compoundof Formula I or its stereoisomers, pharmaceutically acceptable salts,complexes, hydrates, solvates, tautomers, polymorphs, racemic mixtures,optically active forms and pharmaceutically active derivatives thereof,wherein R₁ is selected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₃₋₆ cycloalkyl,C₁₋₆ alkylamino, C₁₋₆ aminoalkylene, or 4-7 membered saturated orunsaturated carbocyclyl or heterocyclyl ring, wherein the heterocyclylring is optionally substituted with upto three heteroatoms independentlyselected from O, N or S, wherein C₁₋₆ alkyl, C₂₋₆ alkenyl, C₃₋₆cycloalkyl, C₁₋₆ alkylamino, C₁₋₆ aminoalkylene, and 4-7 memberedsaturated or unsaturated carbocyclyl or heterocyclyl ring are optionallysubstituted with 1 to 3 groups independently selected from halogen,amino, hydroxyl, SO₃H, O—PO₃H₂, COOR₉, CONHR₉, SO₂NHR₉, methylsulfone,C₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₆ haloalkoxy, C₃₋₆ cycloalkyl, C₃₋₆cycloalkylamino, C₃₋₆ aminocycloalkyl, C₃₋₆ cycloalkylhydroxy, C₁₋₆alkylamino, or 3-7 membered saturated or unsaturated heterocyclyl ringoptionally substituted with upto three heteroatoms independentlyselected from O, N or S; R₉ is selected from hydrogen, or C₁₋₆ alkyl; R₂is chlorine; R₃ is selected from hydrogen, C₁₋₅ alkyl, fluorine, C₁₋₆alkoxy, hydroxyl, or amino; X₁ is N or CR₄; R₄ is selected fromhydrogen, halogen, cyano, C₁₋₅ alkoxy, C₁₋₅ haloalkyl, C₁₋₅ haloalkoxy,or C₁₋₅ alkyl; X₂ is N or CR₅; R₅ is selected from hydrogen, halogen,cyano, C₁₋₅ alkoxy, C₁₋₅ haloalkyl, C₁₋₅ haloalkoxy, or C₁₋₅ alkyl; X₃is N or CR₆; and X₄ is CR₆ when dotted line (----) represents a bond; R₆is selected from hydrogen, cyano, C₁₋₅ alkyl, C₁₋₅ alkylamino, C₁₋₅alkoxy, C₁₋₅ haloalkoxy, or COOH; or X₃ is CH₂ or O; and X₄ is CH₂ whendotted line (----) represents no bond; n₁ is 0 to 2; Y₁, and Y₂ areindependently selected from N or CR₇; R₇ is selected from hydrogen,halogen, cyano, C₁₋₅ alkoxy, C₁₋₅ haloalkyl, C₁₋₅ haloalkoxy, or C₁₋₅alkyl; Z₁ is selected from O, S, NH, or CH₂; and R₈ is selected fromhydrogen, hydroxyl, C₁₋₆ alkyl, or fluorine.

According to an embodiment, the present disclosure relates to a compoundof Formula I or its stereoisomers, pharmaceutically acceptable salts,complexes, hydrates, solvates, tautomers, polymorphs, racemic mixtures,optically active forms and pharmaceutically active derivatives thereof,wherein R₁ is selected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₃₋₆ cycloalkyl,C₁₋₆ alkylamino, C₁₋₆ aminoalkylene, or 4-7 membered saturated orunsaturated carbocyclyl or heterocyclyl ring, wherein the heterocyclylring is optionally substituted with upto three heteroatoms independentlyselected from O, N or S, wherein C₁₋₆ alkyl, C₂₋₆ alkenyl, C₃₋₆cycloalkyl, C₁₋₆ alkylamino, C₁₋₆ aminoalkylene, and 4-7 memberedsaturated or unsaturated carbocyclyl or heterocyclyl ring are optionallysubstituted with 1 to 3 groups independently selected from halogen,amino, hydroxyl, SO₃H, O—PO₃H₂, COOR₉, CONHR₉, SO₂NHR₉, methylsulfone,C₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₆ haloalkoxy, C₃₋₆ cycloalkyl, C₃₋₆cycloalkylamino, C₃₋₆ aminocycloalkyl, C₃₋₆ cycloalkylhydroxy, C₁₋₆alkylamino, or 3-7 membered saturated or unsaturated heterocyclyl ringoptionally substituted with upto three heteroatoms independentlyselected from O, N or S; R₉ is selected from hydrogen, or C₁₋₆ alkyl; R₂is selected from hydrogen, fluorine, chlorine, cyano, C₁₋₅ alkoxy, andhydroxyl; R₃ is hydrogen; X₁ is N or CR₄; R₄ is selected from hydrogen,halogen, cyano, C₁₋₅ alkoxy, C₁₋₅ haloalkyl, C₁₋₅ haloalkoxy, or C₁₋₅alkyl; X₂ is N or CR₅; R₅ is selected from hydrogen, halogen, cyano,C₁₋₅ alkoxy, C₁₋₅ haloalkyl, C₁₋₅ haloalkoxy, or C₁₋₅ alkyl; X₃ is N orCR₆; and X₄ is CR₆ when dotted line (----) represents a bond; R₆ isselected from hydrogen, cyano, C₁₋₅ alkyl, C₁₋₅ alkylamino, C₁₋₅ alkoxy,C₁₋₅ haloalkoxy, or COOH; or X₃ is CH₂ or O; and X₄ is CH₂ when dottedline (----) represents no bond; n₁ is 0 to 2; Y₁, and Y₂ areindependently selected from N or CR₇; R₇ is selected from hydrogen,halogen, cyano, C₁₋₅ alkoxy, C₁₋₅ haloalkyl, C₁₋₅ haloalkoxy, or C₁₋₅alkyl; Z₁ is selected from O, S, NH, or CH₂; and R₈ is selected fromhydrogen, hydroxyl, C₁₋₆ alkyl, or fluorine.

According to an embodiment, the present disclosure relates to a compoundof Formula I or its stereoisomers, pharmaceutically acceptable salts,complexes, hydrates, solvates, tautomers, polymorphs, racemic mixtures,optically active forms and pharmaceutically active derivatives thereof,wherein R₁ is selected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₃₋₆ cycloalkyl,C₁₋₆ alkylamino, C₁₋₆ aminoalkylene, or 4-7 membered saturated orunsaturated carbocyclyl or heterocyclyl ring, wherein the heterocyclylring is optionally substituted with upto three heteroatoms independentlyselected from O, N or S, wherein C₁₋₆ alkyl, C₂₋₆ alkenyl, C₃₋₆cycloalkyl, C₁₋₆ alkylamino, C₁₋₆ aminoalkylene, and 4-7 memberedsaturated or unsaturated carbocyclyl or heterocyclyl ring are optionallysubstituted with 1 to 3 groups independently selected from halogen,amino, hydroxyl, SO₃H, O—PO₃H₂, COOR₉, CONHR₉, SO₂NHR₉, methylsulfone,C₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₆ haloalkoxy, C₃₋₆ cycloalkyl, C₃₋₆cycloalkylamino, C₃₋₆ aminocycloalkyl, C₃₋₆ cycloalkylhydroxy, C₁₋₆alkylamino, or 3-7 membered saturated or unsaturated heterocyclyl ringoptionally substituted with upto three heteroatoms independentlyselected from O, N or S; R₉ is selected from hydrogen, or C₁₋₆ alkyl; R₂is selected from hydrogen, fluorine, chlorine, cyano, C₁₋₅ alkoxy, orhydroxyl; R₃ is hydroxyl; X₁ is N or CR₄; R₄ is selected from hydrogen,halogen, cyano, C₁₋₅ alkoxy, C₁₋₅ haloalkyl, C₁₋₅ haloalkoxy, or C₁₋₅alkyl; X₂ is N or CR₅; R₅ is selected from hydrogen, halogen, cyano,C₁₋₅ alkoxy, C₁₋₅ haloalkyl, C₁₋₅ haloalkoxy, or C₁₋₅ alkyl; X₃ is N orCR₆; and X₄ is CR₆ when dotted line (----) represents a bond; R₆ isselected from hydrogen, cyano, C₁₋₅ alkyl, C₁₋₅ alkylamino, C₁₋₅ alkoxy,C₁₋₅ haloalkoxy, or COOH; or X₃ is CH₂ or O; and X₄ is CH₂ when dottedline (----) represents no bond; n₁ is 0 to 2; Y₁, and Y₂ areindependently selected from N or CR₇; R₇ is selected from hydrogen,halogen, cyano, C₁₋₅ alkoxy, C₁₋₅ haloalkyl, C₁₋₅ haloalkoxy, or C₁₋₅alkyl; Z₁ is selected from O, S, NH, or CH₂; and R₈ is selected fromhydrogen, hydroxyl, C₁₋₆ alkyl, or fluorine.

According to an embodiment, the present disclosure relates to a compoundof Formula I or its stereoisomers, pharmaceutically acceptable salts,complexes, hydrates, solvates, tautomers, polymorphs, racemic mixtures,optically active forms and pharmaceutically active derivatives thereof,wherein R₁ is selected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₃₋₆ cycloalkyl,C₁₋₆ alkylamino, C₁₋₆ aminoalkylene, or 4-7 membered saturated orunsaturated carbocyclyl or heterocyclyl ring, wherein the heterocyclylring is optionally substituted with upto three heteroatoms independentlyselected from O, N or S, wherein C₁₋₆ alkyl, C₂₋₆ alkenyl, C₃₋₆cycloalkyl, C₁₋₆ alkylamino, C₁₋₆ aminoalkylene, and 4-7 memberedsaturated or unsaturated carbocyclyl or heterocyclyl ring are optionallysubstituted with 1 to 3 groups independently selected from halogen,amino, hydroxyl, SO₃H, O—PO₃H₂, COOR₉, CONHR₉, SO₂NHR₉, methylsulfone,C₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₆ haloalkoxy, C₃₋₆ cycloalkyl, C₃₋₆cycloalkylamino, C₃₋₆ aminocycloalkyl, C₃₋₆ cycloalkylhydroxy, C₁₋₆alkylamino, or 3-7 membered saturated or unsaturated heterocyclyl ringoptionally substituted with upto three heteroatoms independentlyselected from O, N or S; R₉ is selected from hydrogen, or C₁₋₆ alkyl; R₂is selected from hydrogen, fluorine, chlorine, cyano, C₁₋₅ alkoxy, andhydroxyl; R₃ is methyl; X₁ is N or CR₄; R₄ is selected from hydrogen,halogen, cyano, C₁₋₅ alkoxy, C₁₋₅ haloalkyl, C₁₋₅ haloalkoxy, or C₁₋₅alkyl; X₂ is N or CR₅; R₅ is selected from hydrogen, halogen, cyano,C₁₋₅ alkoxy, C₁₋₅ haloalkyl, C₁₋₅ haloalkoxy, or C₁₋₅ alkyl; X₃ is N orCR₆; and X₄ is CR₆ when dotted line (----) represents a bond; R₆ isselected from hydrogen, cyano, C₁₋₅ alkyl, C₁₋₅ alkylamino, C₁₋₅ alkoxy,C₁₋₅ haloalkoxy, or COOH; or X₃ is CH₂ or O; and X₄ is CH₂ when dottedline (----) represents no bond; n₁ is 0 to 2; Y₁, and Y₂ areindependently selected from N or CR₇; R₇ is selected from hydrogen,halogen, cyano, C₁₋₅ alkoxy, C₁₋₅ haloalkyl, C₁₋₅ haloalkoxy, or C₁₋₅alkyl; Z₁ is selected from O, S, NH, or CH₂; and R₈ is selected fromhydrogen, hydroxyl, C₁₋₆ alkyl, or fluorine.

According to an embodiment, the present disclosure relates to a compoundof Formula I or its stereoisomers, pharmaceutically acceptable salts,complexes, hydrates, solvates, tautomers, polymorphs, racemic mixtures,optically active forms and pharmaceutically active derivatives thereof,wherein R₁ is selected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₃₋₆ cycloalkyl,C₁₋₆ alkylamino, C₁₋₆ aminoalkylene, or 4-7 membered saturated orunsaturated carbocyclyl or heterocyclyl ring, wherein the heterocyclylring is optionally substituted with upto three heteroatoms independentlyselected from O, N or S, wherein C₁₋₆ alkyl, C₂₋₆ alkenyl, C₃₋₆cycloalkyl, C₁₋₆ alkylamino, C₁₋₆ aminoalkylene, and 4-7 memberedsaturated or unsaturated carbocyclyl or heterocyclyl ring are optionallysubstituted with 1 to 3 groups independently selected from halogen,amino, hydroxyl, SO₃H, O—PO₃H₂, COOR₉, CONHR₉, SO₂NHR₉, methylsulfone,C₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₆ haloalkoxy, C₃₋₆ cycloalkyl, C₃₋₆cycloalkylamino, C₃₋₆ aminocycloalkyl, C₃₋₆ cycloalkylhydroxy, C₁₋₆alkylamino, or 3-7 membered saturated or unsaturated heterocyclyl ringoptionally substituted with upto three heteroatoms independentlyselected from O, N or S; R₉ is selected from hydrogen, or C₁₋₆ alkyl; R₂is selected from hydrogen, fluorine, chlorine, cyano, C₁₋₅ alkoxy, andhydroxyl; R₃ is selected from hydrogen, C₁₋₅ alkyl, fluorine, C₁₋₆alkoxy, hydroxyl, or amino; X₁ is N or CR₄; R₄ is selected fromhydrogen, halogen, cyano, C₁₋₅ alkoxy, C₁₋₅ haloalkyl, C₁₋₅ haloalkoxy,or C₁₋₅ alkyl; X₂ is N or CR₅; R₅ is selected from hydrogen, halogen,cyano, C₁₋₅ alkoxy, C₁₋₅ haloalkyl, C₁₋₅ haloalkoxy, or C₁₋₅ alkyl; X₃is N or CR₆; and X₄ is CR₆ when dotted line (----) represents a bond; R₆is selected from hydrogen, cyano, C₁₋₅ alkyl, C₁₋₅ alkylamino, C₁₋₅alkoxy, C₁₋₅ haloalkoxy, or COOH; or X₃ is CH₂ or O; and X₄ is CH₂ whendotted line (----) represents no bond; n₁ is 0; Y₁, and Y₂ areindependently selected from N or CR₇; R₇ is selected from hydrogen,halogen, cyano, C₁₋₅ alkoxy, C₁₋₅ haloalkyl, C₁₋₅ haloalkoxy, or C₁₋₅alkyl; Z₁ is selected from O, S, NH, or CH₂; and R₈ is selected fromhydrogen, hydroxyl, C₁₋₆ alkyl, or fluorine.

According to an embodiment, the present disclosure relates to a compoundof Formula I or its stereoisomers, pharmaceutically acceptable salts,complexes, hydrates, solvates, tautomers, polymorphs, racemic mixtures,optically active forms and pharmaceutically active derivatives thereof,wherein R₁ is selected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₃₋₆ cycloalkyl,C₁₋₆ alkylamino, C₁₋₆ aminoalkylene, or 4-7 membered saturated orunsaturated carbocyclyl or heterocyclyl ring, wherein the heterocyclylring is optionally substituted with upto three heteroatoms independentlyselected from O, N or S, wherein C₁₋₆ alkyl, C₂₋₆ alkenyl, C₃₋₆cycloalkyl, C₁₋₆ alkylamino, C₁₋₆ aminoalkylene, and 4-7 memberedsaturated or unsaturated carbocyclyl or heterocyclyl ring are optionallysubstituted with 1 to 3 groups independently selected from halogen,amino, hydroxyl, SO₃H, O—PO₃H₂, COOR₉, CONHR₉, SO₂NHR₉, methylsulfone,C₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₆ haloalkoxy, C₃₋₆ cycloalkyl, C₃₋₆cycloalkylamino, C₃₋₆ aminocycloalkyl, C₃₋₆ cycloalkylhydroxy, C₁₋₆alkylamino, or 3-7 membered saturated or unsaturated heterocyclyl ringoptionally substituted with upto three heteroatoms independentlyselected from O, N or S; R₉ is selected from hydrogen, or C₁₋₆ alkyl; R₂is selected from hydrogen, fluorine, chlorine, cyano, C₁₋₅ alkoxy, orhydroxyl; R₃ is selected from hydrogen, C₁₋₅ alkyl, fluorine, C₁₋₆alkoxy, hydroxyl, or amino; X₁ is N or CR₄; R₄ is selected fromhydrogen, halogen, cyano, C₁₋₅ alkoxy, C₁₋₅ haloalkyl, C₁₋₅ haloalkoxy,or C₁₋₅ alkyl; X₂ is N or CR₅; R₅ is selected from hydrogen, halogen,cyano, C₁₋₅ alkoxy, C₁₋₅ haloalkyl, C₁₋₅ haloalkoxy, or C₁₋₅ alkyl; X₃is N or CR₆; and X₄ is CR₆ when dotted line (----) represents a bond; R₆is selected from hydrogen, cyano, C₁₋₅ alkyl, C₁₋₅ alkylamino, C₁₋₅alkoxy, C₁₋₅ haloalkoxy, or COOH; or X₃ is CH₂ or O; and X₄ is CH₂ whendotted line (----) represents no bond; n₁ is 1; Y₁, and Y₂ areindependently selected from N or CR₇; R₇ is selected from hydrogen,halogen, cyano, C₁₋₅ alkoxy, C₁₋₅ haloalkyl, C₁₋₅ haloalkoxy, or C₁₋₅alkyl; Z₁ is selected from O, S, NH, or CH₂; and R₈ is selected fromhydrogen, hydroxyl, C₁₋₆ alkyl, or fluorine.

According to an embodiment, the present disclosure relates to a compoundof Formula I or its stereoisomers, pharmaceutically acceptable salts,complexes, hydrates, solvates, tautomers, polymorphs, racemic mixtures,optically active forms and pharmaceutically active derivatives thereof,wherein R₁ is selected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₃₋₆ cycloalkyl,C₁₋₆ alkylamino, C₁₋₆ aminoalkylene, or 4-7 membered saturated orunsaturated carbocyclyl or heterocyclyl ring, wherein the heterocyclylring is optionally substituted with upto three heteroatoms independentlyselected from O, N or S, wherein C₁₋₆ alkyl, C₂₋₆ alkenyl, C₃₋₆cycloalkyl, C₁₋₆ alkylamino, C₁₋₆ aminoalkylene, and 4-7 memberedsaturated or unsaturated carbocyclyl or heterocyclyl ring are optionallysubstituted with 1 to 3 groups independently selected from halogen,amino, hydroxyl, SO₃H, O—PO₃H₂, COOR₉, CONHR₉, SO₂NHR₉, methylsulfone,C₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₆ haloalkoxy, C₃₋₆ cycloalkyl, C₃₋₆cycloalkylamino, C₃₋₆ aminocycloalkyl, C₃₋₆ cycloalkylhydroxy, C₁₋₆alkylamino, or 3-7 membered saturated or unsaturated heterocyclyl ringoptionally substituted with upto three heteroatoms independentlyselected from O, N or S; R₉ is selected from hydrogen, or C₁₋₆ alkyl; R₂is selected from hydrogen, fluorine, chlorine, C₁₋₄ alkoxy, cyano, orhydroxyl; R₃ is selected from hydrogen, fluorine, C₁₋₄ alkoxy, hydroxyl,or amino; X₁ is N or CR₄; R₄ is selected from hydrogen, halogen, cyano,C₁₋₄ alkoxy, C₁₋₄ haloalkyl, C₁₋₄ haloalkoxy, or C₁₋₄ alkyl; X₂ is N orCR₅; R₅ is selected from hydrogen, halogen, cyano, C₁₋₄ alkoxy, C₁₋₄haloalkyl, C₁₋₄ haloalkoxy, or C₁₋₄ alkyl; X₃ is N or CR₆; and X₄ is CR₆when dotted line (----) represents a bond; R₆ is selected from hydrogen,cyano, C₁₋₄ alkyl, C₁₋₄ alkylamino, C₁₋₄ alkoxy, C₁₋₄ haloalkoxy, orCOOH; or X₃ is CH₂ or O; and X₄ is CH₂ when dotted line (----)represents no bond; n₁ is 0 to 2; Y₁, and Y₂ are independently selectedfrom N or CR₇; R₇ is selected from hydrogen, halogen, cyano, C₁₋₄alkoxy, C₁₋₄ haloalkyl, C₁₋₄ haloalkoxy, or C₁₋₄ alkyl; Z₁ is selectedfrom O, S, NH, or CH₂; and R₈ is selected from hydrogen, hydroxyl, C₁₋₆alkyl, or fluorine.

According to an embodiment, the present disclosure relates to a compoundof Formula I or its stereoisomers, pharmaceutically acceptable salts,complexes, hydrates, solvates, tautomers, polymorphs, racemic mixtures,optically active forms and pharmaceutically active derivatives thereof,wherein R₁ is selected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₃₋₆ cycloalkyl,C₁₋₆ alkylamino, C₁₋₆ aminoalkylene, or 4-7 membered saturated orunsaturated carbocyclyl or heterocyclyl ring, wherein the heterocyclylring is optionally substituted with upto three heteroatoms independentlyselected from O, N or S, wherein C₁₋₆ alkyl, C₂₋₆ alkenyl, C₃₋₆cycloalkyl, C₁₋₆ alkylamino, C₁₋₆ aminoalkylene, and 4-7 memberedsaturated or unsaturated carbocyclyl or heterocyclyl ring are optionallysubstituted with 1 to 3 groups independently selected from halogen,amino, hydroxyl, SO₃H, O—PO₃H₂, COOR₉, CONHR₉, SO₂NHR₉, methylsulfone,C₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₆ haloalkoxy, C₃₋₆ cycloalkyl, C₃₋₆cycloalkylamino, C₃₋₆ aminocycloalkyl, C₃₋₆ cycloalkylhydroxy, C₁₋₆alkylamino, or 3-7 membered saturated or unsaturated heterocyclyl ringoptionally substituted with upto three heteroatoms independentlyselected from O, N or S; R₉ is selected from hydrogen, or C₁₋₆ alkyl; R₂is selected from hydrogen, fluorine, chlorine, C₁₋₄ alkoxy, cyano, orhydroxyl; R₃ is selected from hydrogen, fluorine, C₁₋₄ alkoxy, hydroxyl,or amino; X₁ is N or CR₄; R₄ is selected from hydrogen, halogen, cyano,C₁₋₄ alkoxy, C₁₋₄ haloalkyl, C₁₋₄ haloalkoxy, or C₁₋₄ alkyl; X₂ is N orCR₅; R₅ is selected from hydrogen, halogen, cyano, C₁₋₄ alkoxy, C₁₋₄haloalkyl, C₁₋₄ haloalkoxy, or C₁₋₄ alkyl; X₃ is N or CR₆; and X₄ is CR₆when dotted line (----) represents a bond; R₆ is selected from hydrogen,cyano, C₁₋₄ alkyl, C₁₋₄ alkylamino, C₁₋₄ alkoxy, C₁₋₄ haloalkoxy, orCOOH; or X₃ is CH₂ or O; and X₄ is CH₂ when dotted line (----)represents no bond; n₁ is 0 or 1; Y₁, and Y₂ are independently selectedfrom N or CR₇; R₇ is selected from hydrogen, halogen, cyano, C₁₋₄alkoxy, C₁₋₄ haloalkyl, C₁₋₄ haloalkoxy, or C₁₋₄ alkyl; Z₁ is selectedfrom O, S, NH, or CH₂; and R₈ is selected from hydrogen, hydroxyl, C₁₋₆alkyl, or fluorine.

According to an embodiment, the present disclosure relates to a compoundof Formula I or its stereoisomers, pharmaceutically acceptable salts,complexes, hydrates, solvates, tautomers, polymorphs, racemic mixtures,optically active forms and pharmaceutically active derivatives thereof,wherein R₁ is selected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₃₋₆ cycloalkyl,C₁₋₆ alkylamino, C₁₋₆ aminoalkylene, or 4-7 membered saturated orunsaturated carbocyclyl or heterocyclyl ring, wherein the heterocyclylring is optionally substituted with upto three heteroatoms independentlyselected from O, N or S, wherein C₁₋₆ alkyl, C₂₋₆ alkenyl, C₃₋₆cycloalkyl, C₁₋₆ alkylamino, C₁₋₆ aminoalkylene, and 4-7 memberedsaturated or unsaturated carbocyclyl or heterocyclyl ring are optionallysubstituted with 1 to 3 groups independently selected from halogen,amino, hydroxyl, SO₃H, O—PO₃H₂, COOR₉, CONHR₉, SO₂NHR₉, methylsulfone,C₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₆ haloalkoxy, C₃₋₆ cycloalkyl, C₃₋₆cycloalkylamino, C₃₋₆ aminocycloalkyl, C₃₋₆ cycloalkylhydroxy, C₁₋₆alkylamino, or 3-7 membered saturated or unsaturated heterocyclyl ringoptionally substituted with upto three heteroatoms independentlyselected from O, N or S; R₉ is selected from hydrogen, or C₁₋₆ alkyl; R₂is selected from hydrogen, fluorine, chlorine, C₁₋₄ alkoxy, cyano, orhydroxyl; R₃ is selected from hydrogen, fluorine, C₁₋₄ alkoxy, hydroxyl,or amino; X₁ is N or CR₄; R₄ is selected from hydrogen, halogen, cyano,C₁₋₄ alkoxy, C₁₋₄ haloalkyl, C₁₋₄ haloalkoxy, or C₁₋₄ alkyl; X₂ is N orCR₅; R₅ is selected from hydrogen, halogen, cyano, C₁₋₄ alkoxy, C₁₋₄haloalkyl, C₁₋₄ haloalkoxy, or C₁₋₄ alkyl; X₃ is N or CR₆; and X₄ is CR₆when dotted line (----) represents a bond; R₆ is selected from hydrogen,cyano, C₁₋₄ alkyl, C₁₋₄ alkylamino, C₁₋₄ alkoxy, C₁₋₄ haloalkoxy, orCOOH; or X₃ is CH₂ or O; and X₄ is CH₂ when dotted line (----)represents no bond; n₁ is 0; Y₁, and Y₂ are independently selected fromN or CR₇; R₇ is selected from hydrogen, halogen, cyano, C₁₋₄ alkoxy,C₁₋₄ haloalkyl, C₁₋₄ haloalkoxy, or C₁₋₄ alkyl; Z₁ is selected from O,S, NH, or CH₂; and R₈ is selected from hydrogen, hydroxyl, C₁₋₆ alkyl,or fluorine.

According to an embodiment, the present disclosure relates to a compoundof Formula I or its stereoisomers, pharmaceutically acceptable salts,complexes, hydrates, solvates, tautomers, polymorphs, racemic mixtures,optically active forms and pharmaceutically active derivatives thereof,wherein R₁ is selected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₃₋₆ cycloalkyl,C₁₋₆ alkylamino, C₁₋₆ aminoalkylene, or 4-7 membered saturated orunsaturated carbocyclyl or heterocyclyl ring, wherein the heterocyclylring is optionally substituted with upto three heteroatoms independentlyselected from O, N or S, wherein C₁₋₆ alkyl, C₂₋₆ alkenyl, C₃₋₆cycloalkyl, C₁₋₆ alkylamino, C₁₋₆ aminoalkylene, and 4-7 memberedsaturated or unsaturated carbocyclyl or heterocyclyl ring are optionallysubstituted with 1 to 3 groups independently selected from halogen,amino, hydroxyl, SO₃H, O—PO₃H₂, COOR₉, CONHR₉, SO₂NHR₉, methylsulfone,C₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₆ haloalkoxy, C₃₋₆ cycloalkyl, C₃₋₆cycloalkylamino, C₃₋₆ aminocycloalkyl, C₃₋₆ cycloalkylhydroxy, C₁₋₆alkylamino, or 3-7 membered saturated or unsaturated heterocyclyl ringoptionally substituted with upto three heteroatoms independentlyselected from O, N or S; R₉ is selected from hydrogen, or C₁₋₆ alkyl; R₂is selected from hydrogen, fluorine, chlorine, C₁₋₄ alkoxy, cyano, orhydroxyl; R₃ is selected from hydrogen, fluorine, C₁₋₄ alkoxy, hydroxyl,or amino; X₁ is N or CR₄; R₄ is selected from hydrogen, halogen, cyano,C₁₋₄ alkoxy, C₁₋₄ haloalkyl, C₁₋₄ haloalkoxy, or C₁₋₄ alkyl; X₂ is N orCR₅; R₅ is selected from hydrogen, halogen, cyano, C₁₋₄ alkoxy, C₁₋₄haloalkyl, C₁₋₄ haloalkoxy, or C₁₋₄ alkyl; X₃ is N or CR₆; and X₄ is CR₆when dotted line (----) represents a bond; R₆ is selected from hydrogen,cyano, C₁₋₄ alkyl, C₁₋₄ alkylamino, C₁₋₄ alkoxy, C₁₋₄ haloalkoxy, orCOOH; or X₃ is CH₂ or O; and X₄ is CH₂ when dotted line (----)represents no bond; n₁ is 1; Y₁, and Y₂ are independently selected fromN or CR₇; R₇ is selected from hydrogen, halogen, cyano, C₁₋₄ alkoxy,C₁₋₄ haloalkyl, C₁₋₄ haloalkoxy, or C₁₋₄ alkyl; Z₁ is selected from O,S, NH, or CH₂; and R₈ is selected from hydrogen, hydroxyl, C₁₋₆ alkyl,or fluorine.

According to an embodiment, the present disclosure relates to a compoundof Formula I or its stereoisomers, pharmaceutically acceptable salts,complexes, hydrates, solvates, tautomers, polymorphs, racemic mixtures,optically active forms and pharmaceutically active derivatives thereof,wherein R₁ is selected from C₁₋₅ alkyl, C₂₋₅ alkenyl, C₃₋₅ cycloalkyl,C₁₋₅ alkylamino, C₁₋₅ aminoalkylene, or 4-7 membered saturated orunsaturated carbocyclyl or heterocyclyl ring, wherein the heterocyclylring is optionally substituted with upto three heteroatoms independentlyselected from O, N or S, wherein C₁₋₅ alkyl, C₂₋₅ alkenyl, C₃₋₅cycloalkyl, C₁₋₅ alkylamino, C₁₋₅ aminoalkylene, and 4-7 memberedsaturated or unsaturated carbocyclyl or heterocyclyl ring are optionallysubstituted with 1 to 3 groups independently selected from halogen,amino, hydroxyl, SO₃H, O—PO₃H₂, COOR₉, CONHR₉, SO₂NHR₉, methylsulfone,C₁₋₅ alkyl, C₁₋₅ alkoxy, C₁₋₅ haloalkoxy, C₃₋₅ cycloalkyl, C₃₋₅cycloalkylamino, C₃₋₅ aminocycloalkyl, C₃₋₆ cycloalkylhydroxy, C₁₋₅alkylamino, or 3-7 membered saturated or unsaturated heterocyclyl ringoptionally substituted with upto three heteroatoms independentlyselected from O, N or S; R₉ is selected from hydrogen, or C₁₋₆ alkyl; R₂is selected from hydrogen, fluorine, chlorine, C₁₋₃ alkoxy, cyano, orhydroxyl; R₃ is selected from hydrogen, fluorine, C₁₋₃ alkoxy, hydroxyl,or amino; X₁ is N or CR₄; R₄ is selected from hydrogen, halogen, cyano,C₁₋₃ alkoxy, C₁₋₃ haloalkyl, C₁₋₃ haloalkoxy, or C₁₋₃ alkyl; X₂ is N orCR₅; R₅ is selected from hydrogen, halogen, cyano, C₁₋₃ alkoxy, C₁₋₃haloalkyl, C₁₋₃ haloalkoxy, or C₁₋₃ alkyl; X₃ is N or CR₆; and X₄ is CR₆when dotted line (----) represents a bond; R₆ is selected from hydrogen,cyano, C₁₋₃ alkyl, C₁₋₃ alkylamino, C₁₋₃ alkoxy, C₁₋₃ haloalkoxy, orCOOH; or X₃ is CH₂ or O; and X₄ is CH₂ when dotted line (----)represents no bond; n₁ is 0 to 2; Y₁, and Y₂ are independently selectedfrom N or CR₇; R₇ is selected from hydrogen, halogen, cyano, C₁₋₄alkoxy, C₁₋₄ haloalkyl, C₁₋₄ haloalkoxy, or C₁₋₄ alkyl; Z₁ is selectedfrom O, S, NH, or CH₂; and R₈ is selected from hydrogen, hydroxyl, C₁₋₆alkyl, or fluorine.

According to an embodiment, the present disclosure relates to a compoundof Formula I or its stereoisomers, pharmaceutically acceptable salts,complexes, hydrates, solvates, tautomers, polymorphs, racemic mixtures,optically active forms and pharmaceutically active derivatives thereof,wherein R₁ is selected from C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₃₋₄ cycloalkyl,C₁₋₄ alkylamino, or 4-7 membered saturated carbocyclyl or heterocyclylring, wherein the heterocyclyl ring is optionally substituted with uptothree heteroatoms independently selected from O, N or S, wherein C₁₋₄alkyl, C₁₋₄ haloalkyl, C₃₋₄ cycloalkyl, C₁₋₄ alkylamino, and 4-7membered saturated carbocyclyl or heterocyclyl ring are optionallysubstituted with 1 to 3 groups independently selected from halogen,amino, hydroxyl, O—PO₃H₂, C₁₋₄ alkyl, C₁₋₄ alkoxy, C₁₋₄ haloalkoxy, C₃₋₅cycloalkyl, C₃₋₅ cycloalkylamino, C₃₋₅ aminocycloalkyl, C₃₋₆cycloalkylhydroxy, C₁₋₄ alkylamino, or 3-7 membered saturated orunsaturated heterocyclyl ring optionally substituted with upto threeheteroatoms independently selected from O, N or S; R₂ is selected fromhydrogen, fluorine, chlorine, C₁₋₂ alkoxy, cyano, or hydroxyl; R₃ isselected from hydrogen, fluorine, C₁₋₂ alkoxy, hydroxyl, or amino; X₁ isN or CR₄; R₄ is selected from hydrogen, halogen, cyano, C₁₋₂ alkoxy,C₁₋₂ haloalkyl, C₁₋₂ haloalkoxy, or C₁₋₂ alkyl; X₂ is N or CR₅; R₅ isselected from hydrogen, halogen, cyano, C₁₋₂ alkoxy, C₁₋₂ haloalkyl,C₁₋₂ haloalkoxy, or C₁₋₂ alkyl; X₃ is N or CR₆; and X₄ is CR₆ whendotted line (----) represents a bond; R₆ is selected from hydrogen,cyano, C₁₋₂ alkyl, C₁₋₃ alkylamino, C₁₋₂ alkoxy, C₁₋₂ haloalkoxy, orCOOH; or X₃ is CH₂ or O; and X₃ is CH₂ when dotted line (----)represents no bond; n₁ is 0 or 1; Y₁, and Y₂ are independently selectedfrom N or CR₇; R₇ is selected from hydrogen, halogen, cyano, C₁₋₂alkoxy, C₁₋₂ haloalkyl, C₁₋₂ haloalkoxy, or C₁₋₂ alkyl; Z₁ is selectedfrom O, S, NH, or CH₂; and R₈ is selected from hydrogen, hydroxyl, C₁₋₆alkyl, or fluorine.

According to an embodiment, the present disclosure relates to a compoundof Formula I or its stereoisomers, pharmaceutically acceptable salts,complexes, hydrates, solvates, tautomers, polymorphs, racemic mixtures,optically active forms and pharmaceutically active derivatives thereof,wherein R₁ is selected from C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₃₋₄ cycloalkyl,C₁₋₄ alkylamino, or 4-6 membered saturated carbocyclyl or heterocyclylring, wherein the heterocyclyl ring is optionally substituted with uptothree heteroatoms independently selected from O, N or S, wherein C₁₋₄alkyl, C₁₋₄ haloalkyl, C₃₋₄ cycloalkyl, C₁₋₄ alkylamino, and 4-6membered saturated carbocyclyl or heterocyclyl ring are optionallysubstituted with 1 to 3 groups independently selected from halogen,amino, hydroxyl, O—PO₃H₂, C₁₋₄ alkyl, C₁₋₄ alkoxy, C₁₋₄ haloalkoxy, C₃₋₄cycloalkyl, C₃₋₅ cycloalkylamino, C₃₋₅ aminocycloalkyl, C₃₋₆cycloalkylhydroxy, C₁₋₄ alkylamino, or 3-5 membered saturated orunsaturated heterocyclyl ring optionally substituted with upto threeheteroatoms independently selected from O, N or S; R₂ is selected fromhydrogen, fluorine, chlorine, C₁₋₂ alkoxy, cyano, or hydroxyl; R₃ isselected from hydrogen, fluorine, C₁₋₂ alkoxy, hydroxyl, or amino; X₁ isN or CR₄; R₄ is selected from hydrogen, halogen, cyano, C₁₋₂ alkoxy,C₁₋₂ haloalkyl, C₁₋₂ haloalkoxy, or C₁₋₂ alkyl; X₂ is N or CR₅; R₅ isselected from hydrogen, halogen, cyano, C₁₋₂ alkoxy, C₁₋₂ haloalkyl,C₁₋₂ haloalkoxy, or C₁₋₂ alkyl; X₃ is N or CR₆; and X₄ is CR₆ whendotted line (----) represents a bond; R₆ is selected from hydrogen,cyano, C₁₋₂ alkyl, C₁₋₃ alkylamino, C₁₋₂ alkoxy, C₁₋₂ haloalkoxy, orCOOH; or X₃ is CH₂ or O; and X₃ is CH₂ when dotted line (----)represents no bond; n₁ is 0 or 1; Y₁, and Y₂ are independently selectedfrom N or CR₇; R₇ is selected from hydrogen, halogen, cyano, C₁₋₂alkoxy, C₁₋₂ haloalkyl, C₁₋₂ haloalkoxy, or C₁₋₂ alkyl; Z₁ is selectedfrom O, S, NH, or CH₂; and R₈ is selected from hydrogen, hydroxyl, C₁₋₆alkyl, or fluorine.

According to an embodiment, the present disclosure relates to a compoundof Formula I or its stereoisomers, pharmaceutically acceptable salts,complexes, hydrates, solvates, tautomers, polymorphs, racemic mixtures,optically active forms and pharmaceutically active derivatives thereof,wherein R₁ is selected from C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₃₋₄ cycloalkyl,C₁₋₄ alkylamino, or 4-7 membered saturated carbocyclyl or heterocyclylring, wherein the heterocyclyl ring is optionally substituted with uptothree heteroatoms independently selected from O, N or S, wherein C₁₋₄alkyl, C₁₋₄ haloalkyl, C₃₋₄ cycloalkyl, C₁₋₄ alkylamino, and 4-7membered saturated carbocyclyl or heterocyclyl ring are optionallysubstituted with 1 to 3 groups independently selected from halogen,amino, hydroxyl, O—PO₃H₂, C₁₋₄ alkyl, C₁₋₄ alkoxy, C₁₋₄ haloalkoxy, C₃₋₅cycloalkyl, C₃₋₅ cycloalkylamino, C₃₋₅ aminocycloalkyl, C₃₋₆cycloalkylhydroxy, C₁₋₄ alkylamino, or 3-7 membered saturated orunsaturated heterocyclyl ring optionally substituted with upto threeheteroatoms independently selected from O, N or S; R₂ is selected fromhydrogen, fluorine, chlorine, C₁ alkoxy, cyano, or hydroxyl; R₃ isselected from hydrogen, fluorine, C₁ alkoxy, hydroxyl, or amino; X₁ is Nor CR₄; R₄ is selected from hydrogen, halogen, cyano, C₁ alkoxy, or C₁alkyl; X₂ is N or CR₅; R₅ is selected from hydrogen, halogen, cyano, C₁alkoxy, C₁ haloalkyl, C₁ haloalkoxy, or C₁ alkyl; X₃ is N or CR₆; and X₄is CR₆ when dotted line (----) represents a bond; R₆ is selected fromhydrogen, cyano, C₁₋₂ alkyl, C₁₋₃ alkylamino, C₁₋₂ alkoxy, C₁₋₂haloalkoxy, or COOH; or X₃ is CH₂ or O; and X₃ is CH₂ when dotted line(----) represents no bond; n₁ is 0 or 1; Y₁, and Y₂ are independentlyselected from N or CR₇; R₇ is selected from hydrogen, halogen, cyano,C₁₋₂ alkoxy, C₁₋₂ haloalkyl, C₁₋₂ haloalkoxy, or C₁₋₂ alkyl; Z₁ isselected from O, S, NH, or CH₂; and R₈ is selected from hydrogen,hydroxyl, C₁₋₆ alkyl, or fluorine.

According to an embodiment, the present disclosure relates to a compoundof Formula I or its stereoisomers, pharmaceutically acceptable salts,complexes, hydrates, solvates, tautomers, polymorphs, racemic mixtures,optically active forms and pharmaceutically active derivatives thereof,wherein R₁ is selected from C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₃₋₄ cycloalkyl,C₁₋₄ alkylamino, or 4-7 membered saturated carbocyclyl or heterocyclylring, wherein the heterocyclyl ring is optionally substituted with uptothree heteroatoms independently selected from O, N or S, wherein C₁₋₄alkyl, C₁₋₄ haloalkyl, C₃₋₄ cycloalkyl, C₁₋₄ alkylamino, and 4-7membered saturated carbocyclyl or heterocyclyl ring are optionallysubstituted with 1 to 3 groups independently selected from halogen,amino, hydroxyl, O—PO₃H₂, C₁₋₄ alkyl, C₁₋₄ alkoxy, C₁₋₄ haloalkoxy, C₃₋₅cycloalkyl, C₃₋₅ cycloalkylamino, C₃₋₅ aminocycloalkyl, C₃₋₆cycloalkylhydroxy, C₁₋₄ alkylamino, or 3-7 membered saturated orunsaturated heterocyclyl ring optionally substituted with upto threeheteroatoms independently selected from O, N or S; R₂ is selected fromhydrogen, fluorine, C₁₋₂ alkoxy, cyano, or hydroxyl; R₃ is selected fromhydrogen, fluorine, C₁₋₂ alkoxy, hydroxyl, or amino; X₁ is N or CR₄; R₄is selected from hydrogen, halogen, cyano, C₁₋₂ alkoxy, C₁₋₂ haloalkyl,C₁₋₂ haloalkoxy, or C₁₋₂ alkyl; X₂ is N or CR₅; R₅ is selected fromhydrogen, halogen, cyano, C₁₋₂ alkoxy, C₁₋₂ haloalkyl, C₁₋₂ haloalkoxy,or C₁₋₂ alkyl; X₃ is N or CR₆; and X₄ is CR₆ when dotted line (----)represents a bond; R₆ is selected from hydrogen, cyano, C₁ alkyl, C₁₋₃alkylamino, C₁ alkoxy, C₁ haloalkoxy, or COOH; or X₃ is CH₂ or O; and X₃is CH₂ when dotted line (----) represents no bond; n₁ is 0 or 1; Y₁, andY₂ are independently selected from N or CR₇; R₇ is selected fromhydrogen, halogen, cyano, C₁ alkoxy, or C₁ alkyl; Z₁ is selected from O,S, NH, or CH₂; and R₈ is selected from hydrogen, hydroxyl, C₁₋₆ alkyl,or fluorine.

According to an embodiment, the present disclosure relates to a compoundof Formula I or its stereoisomers, pharmaceutically acceptable salts,complexes, hydrates, solvates, tautomers, polymorphs, racemic mixtures,optically active forms and pharmaceutically active derivatives thereof,wherein R₁ is selected from CH₃, CH₂CH₃, CH(CH₃)₂, cyclopropyl,cyclobutyl, CH₂CF₃, CH₂CHFCH₃, CH₂CF₂CH₃, CH₂CH(OH)CH₃, CH₂CH₂OH,CH₂CH₂OCH₃, CH₂CH(OCH₃)CH₃, CH₂CH₂NH₂, CH₂CH₂NHCH₃, CH₂CH(NH₂)CH₃,CH₂CH₂N(CH₃)₂, CH₂CHFCH₂NH₂, CH₂CF₂CH₂NH₂,

R₂ is selected from H, F, Cl, OCH₃, CN, or OH; R₃ is selected from H, F,OCH₃, OH, or NH₂; X₁ is N or CR₄; R₄ is selected from H, F, CN, OCH₃, orCH₃; X₂ is N or CR₅; R₅ is selected from H, F, CN, OCH₃, CF₃, OCF₃, orCH₃; X₃ is N or CR₆; and X₄ is CR₆ when dotted line (----) represents abond; R₆ is selected from H, CN, COOH, CH₂NH₂, CH(CH₃)NH₂, CH₂NHCH₃,OCH₃, OCF₃, or CH₃; or X₃ is CH₂ or O; and X₄ is CH₂ when dotted line(----) represents no bond; n₁ is 0 or 1; Y₁, and Y₂ are independentlyselected from N or CR₇; R₇ is selected from H, F, CN, OCH₃, or CH₃; Z₁is selected from O, S, NH, or CH₂; and R₈ is selected from H, OH, C₁₋₆alkyl, or F.

According to an embodiment, the present disclosure relates to a compoundof Formula I or its stereoisomers, pharmaceutically acceptable salts,complexes, hydrates, solvates, tautomers, polymorphs, racemic mixtures,optically active forms and pharmaceutically active derivatives thereof,wherein R₁ is selected from CH₃, CH₂CH₃, CH(CH₃)₂, cyclopropyl,cyclobutyl, CH₂CF₃, CH₂CHFCH₃, CH₂CF₂CH₃, CH₂CH(OH)CH₃, CH₂CH₂OH,CH₂CH₂OCH₃, CH₂CH(OCH₃)CH₃, CH₂CH₂NH₂, CH₂CH₂NHCH₃, CH₂CH(NH₂)CH₃,CH₂CH₂N(CH₃)₂, CH₂CHFCH₂NH₂, CH₂CF₂CH₂NH₂,

R₂ is selected from H, F, Cl, OCH₃, CN, or OH; R₃ is selected from H, F,OCH₃, OH, or NH₂; X₁ is N or CR₄; R₄ is selected from H, F, CN, OCH₃, orCH₃; X₂ is N or CR₅; R₅ is selected from H, F, CN, OCH₃, CF₃, OCF₃, orCH₃; X₃ is N or CR₆; and X₄ is CR₆ when dotted line (----) represents abond; R₆ is selected from H, CN, COOH, CH₂NH₂, CH(CH₃)NH₂, CH₂NHCH₃,OCH₃, OCF₃, or CH₃; or X₃ is CH₂ or O; and X₄ is CH₂ when dotted line(----) represents no bond; n₁ is 0 or 1; Y₁, and Y₂ are independentlyselected from N or CR₇; R₇ is selected from H, F, CN, OCH₃, or CH₃; Z₁is O or S; and R₈ is H.

According to an embodiment, the present disclosure relates to a compoundof Formula I or its stereoisomers, pharmaceutically acceptable salts,complexes, hydrates, solvates, tautomers, polymorphs, racemic mixtures,optically active forms and pharmaceutically active derivatives thereof,wherein R₁ is selected from CH₃, CH₂CH₃, CH(CH₃)₂, cyclopropyl,cyclobutyl, CH₂CF₃, CH₂CHFCH₃, CH₂CF₂CH₃, CH₂CH(OH)CH₃, CH₂CH₂OH,CH₂CH₂OCH₃, CH₂CH(OCH₃)CH₃, CH₂CH₂NH₂, CH₂CH₂NHCH₃, CH₂CH(NH₂)CH₃,CH₂CH₂N(CH₃)₂, CH₂CHFCH₂NH₂, CH₂CF₂CH₂NH₂,

R₂ is selected from H, F, Cl, OCH₃, CN, or OH; R₃ is selected from H, F,OCH₃, OH, or NH₂; X₁ is N or CR₄; R₄ is selected from H, F, CN, OCH₃, orCH₃; X₂ is N or CR₅; R₅ is selected from H, F, CN, OCH₃, CF₃, OCF₃, orCH₃; X₃ is N or CR₆; and X₄ is CR₆ when dotted line (----) represents abond; R₆ is selected from H, CN, COOH, CH₂NH₂, CH(CH₃)NH₂, CH₂NHCH₃,OCH₃, OCF₃, or CH₃; or X₃ is CH₂ or O; and X₄ is CH₂ when dotted line(----) represents no bond; n₁ is 0 or 1; Y₁ is CR₇; R₇ is H; Y₂ is N; Z₁is O or S; and R₈ is H.

According to an embodiment, the present disclosure relates to a compoundof Formula I or its stereoisomers, pharmaceutically acceptable salts,complexes, hydrates, solvates, tautomers, polymorphs, racemic mixtures,optically active forms and pharmaceutically active derivatives thereof,wherein R₁ is selected from CH₃, CH₂CH₃, CH(CH₃)₂, cyclopropyl,cyclobutyl, CH₂CF₃, CH₂CHFCH₃, CH₂CF₂CH₃, CH₂CH(OH)CH₃, CH₂CH₂OH,CH₂CH₂OCH₃, CH₂CH(OCH₃)CH₃, CH₂CH₂NH₂, CH₂CH₂NHCH₃, CH₂CH(NH₂)CH₃,CH₂CH₂N(CH₃)₂, CH₂CHFCH₂NH₂, CH₂CF₂CH₂NH₂,

R₂ is selected from H, F, Cl, OCH₃, CN, or OH; R₃ is selected from H, F,OCH₃, OH, or NH₂; X₁ is N or CR₄; R₄ is selected from H, F, CN, OCH₃, orCH₃; X₂ is N or CR₅; R₅ is selected from H, F, CN, OCH₃, CF₃, OCF₃, orCH₃; X₃ is N or CR₆; and X₄ is CR₆ when dotted line (----) represents abond; R₆ is selected from H, CN, COOH, CH₂NH₂, CH(CH₃)NH₂, CH₂NHCH₃,OCH₃, OCF₃, or CH₃; or X₃ is CH₂ or O; and X₄ is CH₂ when dotted line(----) represents no bond; n₁ is 0 or 1; Y₁ is CR₇; Y₂ is CR₇; R₇ is H;Z₁ is O or S; and R₈ is H.

According to an embodiment, the present disclosure relates to a compoundof Formula I or its stereoisomers, pharmaceutically acceptable salts,complexes, hydrates, solvates, tautomers, polymorphs, racemic mixtures,optically active forms and pharmaceutically active derivatives thereof,wherein R₁ is selected from CH₃, C₂H, or CH₂CH₂OH; R₂ is selected fromH, F, Cl, OCH₃, CN, or OH; R₃ is selected from H, F, OCH₃, OH, or NH₂;X₁ is N or CR₄; R₄ is selected from H, F, CN, OCH₃, or CH₃; X₂ is N orCR₅; R₅ is selected from H, F, CN, OCH₃, CF₃, OCF₃, or CH₃; X₃ is N orCR₆; and X₄ is CR₆ when dotted line (----) represents a bond; R₆ isselected from H, CN, COOH, CH₂NH₂, CH(CH₃)NH₂, CH₂NHCH₃, OCH₃, OCF₃, andCH₃; or X₃ is CH₂ or O; and X₄ is CH₂ when dotted line (----) representsno bond; n₁ is 0 or 1; Y₁, and Y₂ are independently selected from N orCR₇; R₇ is selected from H, F, CN, OCH₃, or CH₃; Z₁ is O or S; and R₈ isH.

According to an embodiment, the present disclosure relates to a compoundof Formula I or its stereoisomers, pharmaceutically acceptable salts,complexes, hydrates, solvates, tautomers, polymorphs, racemic mixtures,optically active forms and pharmaceutically active derivatives thereof,wherein R₁ is selected from CH₃, CH₂CH₃, CH(CH₃)₂, cyclopropyl,cyclobutyl, CH₂CF₃, CH₂CHFCH₃, CH₂CF₂CH₃, CH₂CH(OH)CH₃, CH₂CH₂OH,CH₂CH₂OCH₃, CH₂CH(OCH₃)CH₃, CH₂CH₂NH₂, CH₂CH₂NHCH₃, CH₂CH(NH₂)CH₃,CH₂CH₂N(CH₃)₂, CH₂CHFCH₂NH₂, CH₂CF₂CH₂NH₂,

R₂ is selected from H, F, or C₁; R₃ is selected from H, F, OCH₃, OH, orNH₂; X₁ is N or CR₄; R₄ is selected from H, F, CN, OCH₃, or CH₃; X₂ is Nor CR₅; R₅ is selected from H, F, CN, OCH₃, CF₃, OCF₃, or CH₃; X₃ is Nor CR₆; and X₄ is CR₆ when dotted line (----) represents a bond; R₆ isselected from H, CN, COOH, CH₂NH₂, CH(CH₃)NH₂, CH₂NHCH₃, OCH₃, OCF₃, orCH₃; or X₃ is CH₂ or O; and X₄ is CH₂ when dotted line (----) representsno bond; n₁ is 0 or 1; Y₁, and Y₂ are independently selected from N orCR₇; R₇ is selected from H, F, CN, OCH₃, or CH₃; Z₁ is O or S; and R₈ isH.

According to an embodiment, the present disclosure relates to a compoundof Formula I or its stereoisomers, pharmaceutically acceptable salts,complexes, hydrates, solvates, tautomers, polymorphs, racemic mixtures,optically active forms and pharmaceutically active derivatives thereof,wherein R₁ is selected from CH₃, CH₂CH₃, CH(CH₃)₂, cyclopropyl,cyclobutyl, CH₂CF₃, CH₂CHFCH₃, CH₂CF₂CH₃, CH₂CH(OH)CH₃, CH₂CH₂OH,CH₂CH₂OCH₃, CH₂CH(OCH₃)CH₃, CH₂CH₂NH₂, CH₂CH₂NHCH₃, CH₂CH(NH₂)CH₃,CH₂CH₂N(CH₃)₂, CH₂CHFCH₂NH₂, CH₂CF₂CH₂NH₂,

R₂ is selected from H, F, Cl, OCH₃, CN, or OH; R₃ is selected from H, orOH; X₁ is N or CR₄; R₄ is selected from H, F, CN, OCH₃, or CH₃; X₂ is Nor CR₅; R₅ is selected from H, F, CN, OCH₃, CF₃, OCF₃, or CH₃; X₃ is Nor CR₆; and X₄ is CR₆ when dotted line (----) represents a bond; R₆ isselected from H, CN, COOH, CH₂NH₂, CH(CH₃)NH₂, CH₂NHCH₃, OCH₃, OCF₃, orCH₃; or X₃ is CH₂ or O; and X₄ is CH₂ when dotted line (----) representsno bond; n₁ is 0 or 1; Y₁, and Y₂ are independently selected from N orCR₇; R₇ is selected from H, F, CN, OCH₃, or CH₃; Z₁ is O or S; and R₈ isH.

According to an embodiment, the present disclosure relates to a compoundof Formula I or its stereoisomers, pharmaceutically acceptable salts,complexes, hydrates, solvates, tautomers, polymorphs, racemic mixtures,optically active forms and pharmaceutically active derivatives thereof,wherein R₁ is selected from CH₃, CH₂CH₃, CH(CH₃)₂, cyclopropyl,cyclobutyl, CH₂CF₃, CH₂CHFCH₃, CH₂CF₂CH₃, CH₂CH(OH)CH₃, CH₂CH₂OH,CH₂CH₂OCH₃, CH₂CH(OCH₃)CH₃, CH₂CH₂NH₂, CH₂CH₂NHCH₃, CH₂CH(NH₂)CH₃,CH₂CH₂N(CH₃)₂, CH₂CHFCH₂NH₂, CH₂CF₂CH₂NH₂,

R₂ is selected from H, F, Cl, OCH₃, CN, or OH; R₃ is selected from H, F,OCH₃, OH, or NH₂; X₁ is CR₄; R₄ is H; X₂ is N or CR₅; R₅ is selectedfrom H, F, CN, OCH₃, CF₃, OCF₃, or CH₃; X₃ is N or CR₆; and X₄ is CR₆when dotted line (----) represents a bond; R₆ is selected from H, CN,COOH, CH₂NH₂, CH(CH₃)NH₂, CH₂NHCH₃, OCH₃, OCF₃, or CH₃; or X₃ is CH₂ orO; and X₄ is CH₂ when dotted line (----) represents no bond; n₁ is 0 or1; Y₁, and Y₂ are independently selected from N or CR₇; R₇ is selectedfrom H, F, CN, OCH₃, or CH₃; Z₁ is O or S; and R₈ is H.

According to an embodiment, the present disclosure relates to a compoundof Formula I or its stereoisomers, pharmaceutically acceptable salts,complexes, hydrates, solvates, tautomers, polymorphs, racemic mixtures,optically active forms and pharmaceutically active derivatives thereof,wherein R₁ is selected from CH₃, CH₂CH₃, CH(CH₃)₂, cyclopropyl,cyclobutyl, CH₂CF₃, CH₂CHFCH₃, CH₂CF₂CH₃, CH₂CH(OH)CH₃, CH₂CH₂OH,CH₂CH₂OCH₃, CH₂CH(OCH₃)CH₃, CH₂CH₂NH₂, CH₂CH₂NHCH₃, CH₂CH(NH₂)CH₃,CH₂CH₂N(CH₃)₂, CH₂CHFCH₂NH₂, CH₂CF₂CH₂NH₂,

R₂ is selected from H, F, Cl, OCH₃, CN, or OH; R₃ is selected from H, F,OCH₃, OH, or NH₂; X₁ is CR₄; R₄ is H; X₂ is N; X₃ is N or CR₆; and X₄ isCR₆ when dotted line (----) represents a bond; R₆ is selected from H,CN, COOH, CH₂NH₂, CH(CH₃)NH₂, CH₂NHCH₃, OCH₃, OCF₃, or CH₃; or X₃ is CH₂or O; and X₄ is CH₂ when dotted line (----) represents no bond; n₁ is 0or 1; Y₁, and Y₂ are independently selected from N or CR₇; R₇ isselected from H, F, CN, OCH₃, or CH₃; Z₁ is O or S; and R₈ is H.

According to an embodiment, the present disclosure relates to a compoundof Formula I or its stereoisomers, pharmaceutically acceptable salts,complexes, hydrates, solvates, tautomers, polymorphs, racemic mixtures,optically active forms and pharmaceutically active derivatives thereof,wherein R₁ is selected from CH₃, CH₂CH₃, CH(CH₃)₂, cyclopropyl,cyclobutyl, CH₂CF₃, CH₂CHFCH₃, CH₂CF₂CH₃, CH₂CH(OH)CH₃, CH₂CH₂OH,CH₂CH₂OCH₃, CH₂CH(OCH₃)CH₃, CH₂CH₂NH₂, CH₂CH₂NHCH₃, CH₂CH(NH₂)CH₃,CH₂CH₂N(CH₃)₂, CH₂CHFCH₂NH₂, CH₂CF₂CH₂NH₂,

R₂ is selected from H, F, Cl, OCH₃, CN, or OH; R₃ is selected from H, F,OCH₃, OH, or NH₂; X₁ is CR₄; R₄ is H; X₂ is CR₅; R₅ is H or CH₃; X₃ is Nor CR₆; and X₄ is CR₆ when dotted line (----) represents a bond; R₆ isselected from H, CN, COOH, CH₂NH₂, CH(CH₃)NH₂, CH₂NHCH₃, OCH₃, OCF₃, orCH₃; or X₃ is CH₂ or O; and X₄ is CH₂ when dotted line (----) representsno bond; n₁ is 0 or 1; Y₁, and Y₂ are independently selected from N orCR₇; R₇ is selected from H, F, CN, OCH₃, or CH₃; Z₁ is O or S; and R₈ isH.

According to an embodiment, the present disclosure relates to a compoundof Formula I or its stereoisomers, pharmaceutically acceptable salts,complexes, hydrates, solvates, tautomers, polymorphs, racemic mixtures,optically active forms and pharmaceutically active derivatives thereof,wherein R₁ is selected from CH₃, C₂H, or CH₂CH₂OH; R₂ is selected fromH, Cl, or F; R₃ is selected from H, CH₃, and OH; X₁ is CR₄; R₄ is H; X₂is N or CR₅; R₅ is H or CH₃; X₃ is N or CR₆; and X₄ is CR₆ when dottedline (----) represents a bond; R₆ is H or CH₃; or X₃ is CH₂ or 0; and X₄is CH₂ when dotted line (----) represents no bond; n₁ is 0 or 1; Y₁ isCR₇; Y₂ is N or CR₇; R₇ is H; Z₁ is O or S; and R₈ is H.

According to an embodiment, the present disclosure relates to a compoundof Formula I or its stereoisomers, pharmaceutically acceptable salts,complexes, hydrates, solvates, tautomers, polymorphs, racemic mixtures,optically active forms and pharmaceutically active derivatives thereof,wherein R₁ is selected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₃₋₆ cycloalkyl,C₁₋₆ alkylamino, C₁₋₆ aminoalkylene, or 4-7 membered saturated orunsaturated carbocyclyl or heterocyclyl ring, wherein the heterocyclylring is optionally substituted with upto three heteroatoms independentlyselected from O, N or S, wherein C₁₋₆ alkyl, C₂₋₆ alkenyl, C₃₋₆cycloalkyl, C₁₋₆ alkylamino, C₁₋₆ aminoalkylene, and 4-7 memberedsaturated or unsaturated carbocyclyl or heterocyclyl ring are optionallysubstituted with 1 to 3 groups independently selected from halogen,amino, hydroxyl, SO₃H, O—PO₃H₂, COOR₉, CONHR₉, SO₂NHR₉, methylsulfone,C₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₆ haloalkoxy, C₃₋₆ cycloalkyl, C₃₋₆cycloalkylamino, C₃₋₆ aminocycloalkyl, C₃₋₆ cycloalkylhydroxy, C₁₋₆alkylamino, or 3-7 membered saturated or unsaturated heterocyclyl ringoptionally substituted with upto three heteroatoms independentlyselected from O, N or S; and R₉ is selected from hydrogen, or C₁₋₆alkyl.

According to an embodiment, the present disclosure relates to a compoundof Formula I or its stereoisomers, pharmaceutically acceptable salts,complexes, hydrates, solvates, tautomers, polymorphs, racemic mixtures,optically active forms and pharmaceutically active derivatives thereof,wherein R₂ is selected from hydrogen, fluorine, chlorine, cyano, C₁₋₆alkoxy, or hydroxyl.

According to an embodiment, the present disclosure relates to a compoundof Formula I or its stereoisomers, pharmaceutically acceptable salts,complexes, hydrates, solvates, tautomers, polymorphs, racemic mixtures,optically active forms and pharmaceutically active derivatives thereof,wherein R₃ is selected from hydrogen, C₁₋₆ alkyl, fluorine, C₁₋₆ alkoxy,hydroxyl, or amino.

According to an embodiment, the present disclosure relates to a compoundof Formula I or its stereoisomers, pharmaceutically acceptable salts,complexes, hydrates, solvates, tautomers, polymorphs, racemic mixtures,optically active forms and pharmaceutically active derivatives thereof,wherein X₁ is N or CR₄; and R₄ is selected from hydrogen, halogen,cyano, C₁₋₆ alkoxy, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, or C₁₋₆ alkyl.

According to an embodiment, the present disclosure relates to a compoundof Formula I or its stereoisomers, pharmaceutically acceptable salts,complexes, hydrates, solvates, tautomers, polymorphs, racemic mixtures,optically active forms and pharmaceutically active derivatives thereof,wherein X₂ is N or CR₅; and R₅ is selected from hydrogen, halogen,cyano, C₁₋₆ alkoxy, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, or C₁₋₆ alkyl.

According to an embodiment, the present disclosure relates to a compoundof Formula I or its stereoisomers, pharmaceutically acceptable salts,complexes, hydrates, solvates, tautomers, polymorphs, racemic mixtures,optically active forms and pharmaceutically active derivatives thereof,wherein X₃ is N or CR₆; and X₄ is CR₆ when dotted line (----) representsa bond; and R₆ is selected from hydrogen, cyano, C₁₋₆ alkyl, C₁₋₆alkylamino, C₁₋₆ alkoxy, C₁₋₆ haloalkoxy, or COOH; or X₃ is CH₂ or O;and X₄ is CH₂ when dotted line (----) represents no bond.

According to an embodiment, the present disclosure relates to a compoundof Formula I or its stereoisomers, pharmaceutically acceptable salts,complexes, hydrates, solvates, tautomers, polymorphs, racemic mixtures,optically active forms and pharmaceutically active derivatives thereof,wherein n₁ is 0 to 2.

According to an embodiment, the present disclosure relates to a compoundof Formula I or its stereoisomers, pharmaceutically acceptable salts,complexes, hydrates, solvates, tautomers, polymorphs, racemic mixtures,optically active forms and pharmaceutically active derivatives thereof,wherein Y₁, and Y₂ are independently selected from N or CR₇; and R₇ isselected from hydrogen, halogen, cyano, C₁₋₆ alkoxy, C₁₋₆ haloalkyl,C₁₋₆ haloalkoxy, or C₁₋₆ alkyl.

According to an embodiment, the present disclosure relates to a compoundof Formula I or its stereoisomers, pharmaceutically acceptable salts,complexes, hydrates, solvates, tautomers, polymorphs, racemic mixtures,optically active forms and pharmaceutically active derivatives thereof,wherein Z₁ is selected from O, S, NH, or CH₂.

According to an embodiment, the present disclosure relates to a compoundof Formula I or its stereoisomers, pharmaceutically acceptable salts,complexes, hydrates, solvates, tautomers, polymorphs, racemic mixtures,optically active forms and pharmaceutically active derivatives thereof,wherein R₈ is selected from hydrogen, hydroxyl, C₁₋₆ alkyl, or fluorine.

According to an embodiment, the present disclosure relates to a compoundof Formula I or its stereoisomers, pharmaceutically acceptable salts,complexes, hydrates, solvates, tautomers, polymorphs, racemic mixtures,optically active forms and pharmaceutically active derivatives thereof,which is selected from a group consisting of:

-   (S)-6-(5-(((2-((5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridin-4-yl)oxy)ethyl)amino)methyl)-2-oxooxazolidin-3-yl)-2H-pyrido[3,2-b][1,4]oxazin-3(4H)-one    (Compound 1),

-   (S)-6-(5-(((2-((7-fluoro-1-methyl-2-oxo-1,2-dihydroquinolin-8-yl)oxy)ethyl)amino)methyl)-2-oxooxazolidin-3-yl)-2H-pyrazino[2,3-b][1,4]oxazin-3(4H)-one    (Compound 2),

-   (R)-6-(5-(((2-((7-fluoro-1-methyl-2-oxo-1,2-dihydroquinolin-8-yl)oxy)ethyl)amino)methyl)-2-oxooxazolidin-3-yl)-2H-pyrazino[2,3-b][1,4]oxazin-3(4H)-one    (Compound 3),

-   6-((5S)-5-(((1-((7-fluoro-1-methyl-2-oxo-1,2-dihydroquinolin-8-yl)oxy)propan-2-yl)amino)methyl)-2-oxooxazolidin-3-yl)-2H-pyrazino[2,3-b][1,4]oxazin-3(4H)-one    (Compound 4),

-   (S)-6-(5-(((2-((7-fluoro-1,4-dimethyl-2-oxo-1,2-dihydroquinolin-8-yl)oxy)ethyl)amino)methyl)-2-oxooxazolidin-3-yl)-2H-pyrazino[2,3-b][1,4]oxazin-3(4H)-one    (Compound 5),

-   (S)-6-(5-(((2-((3-chloro-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridin-4-yl)oxy)ethyl)amino)methyl)-2-oxooxazolidin-3-yl)-2H-pyrazino[2,3-b][1,4]oxazin-3(4H)-one    (Compound 6),

-   (S)-6-(5-(((2-((6-fluoro-4-methyl-3-oxo-3,4-dihydroquinoxalin-5-yl)oxy)ethyl)amino)methyl)-2-oxooxazolidin-3-yl)-2H-pyrazino[2,3-b][1,4]oxazin-3(4H)-one    (Compound 7),

-   (R)-6-(5-(((2-((6-fluoro-4-methyl-3-oxo-3,4-dihydroquinoxalin-5-yl)oxy)ethyl)amino)methyl)-2-oxooxazolidin-3-yl)-2H-pyrazino[2,3-b][1,4]oxazin-3(4H)-one    (Compound 8),

-   (S)-6-(5-(((2-((6-fluoro-2,4-dimethyl-3-oxo-3,4-dihydroquinoxalin-5-yl)oxy)ethyl)amino)methyl)-2-oxooxazolidin-3-yl)-2H-pyrazino[2,3-b][1,4]oxazin-3(4H)-one    (Compound 9),

-   (S)-5-(((2-((6-fluoro-4-methyl-3-oxo-3,4-dihydroquinoxalin-5-yl)oxy)ethyl)amino)methyl)-3-(3-oxo-3,4-dihydro-2H-pyrazino[2,3-b][1,4]thiazin-6-yl)oxazolidin-2-one    (Compound 10),

According to an embodiment, the present disclosure relates to a compoundof Formula I or its stereoisomers, pharmaceutically acceptable salts,complexes, hydrates, solvates, tautomers, polymorphs, racemic mixtures,optically active forms and pharmaceutically active derivatives thereof,which is selected from a group consisting of:

-   (S)-6-(5-(((2-((4-ethyl-6-fluoro-3-oxo-3,4-dihydroquinoxalin-5-yl)oxy)ethyl)amino)methyl)-2-oxooxazolidin-3-yl)-2H-pyrazino[2,3-b][1,4]oxazin-3(4H)-one    (Compound 11),

-   (S)-6-(5-(((2-((6-fluoro-4,8-dimethyl-3-oxo-3,4-dihydroquinoxalin-5-yl)oxy)ethyl)amino)methyl)-2-oxooxazolidin-3-yl)-2H-pyrazino[2,3-b][1,4]oxazin-3(4H)-one    (Compound 12),

-   6-((5S)-5-(((3-((6-fluoro-4-methyl-3-oxo-3,4-dihydroquinoxalin-5-yl)oxy)-2-hydroxypropyl)amino)methyl)-2-oxooxazolidin-3-yl)-2H-pyrazino[2,3-b][1,4]oxazin-3(4H)-one    (Compound 13),

-   (S)-5-(((2-((7-fluoro-1-(2-hydroxyethyl)-2-oxo-1,2-dihydroquinolin-8-yl)oxy)ethyl)    amino)methyl)-3-(3-oxo-3,4-dihydro-2H-pyrazino[2,3-b][1,4]thiazin-6-yl)oxazolidin-2-one    (Compound 14), and

-   (5S)-5-(((3-((7-fluoro-1-methyl-2-oxo-1,2-dihydroquinolin-8-yl)oxy)-2-hydroxypropyl)amino)    methyl)-3-(3-oxo-3,4-dihydro-2H-pyrazino[2,3-b][1,4]thiazin-6-yl)oxazolidin-2-one    (Compound 15)

According to an embodiment, the present disclosure relates to a compoundof Formula (B) or its stereoisomers, pharmaceutically acceptable salts,complexes, hydrates, solvates, tautomers, polymorphs, racemic mixtures,optically active forms, and pharmaceutically active derivatives thereof,wherein

Y₁, and Y₂ are independently selected from N or CR₇; R₇ is selected fromhydrogen, halogen, cyano, C₁₋₆ alkoxy, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy,or C₁₋₆ alkyl; Z₁ is selected from O, S, NH, or CH₂; and R₈ is selectedfrom hydrogen, hydroxyl, C₁₋₆ alkyl, or fluorine.

According to an embodiment, the present disclosure relates to a compoundof Formula (B) or its stereoisomers, pharmaceutically acceptable salts,complexes, hydrates, solvates, tautomers, polymorphs, racemic mixtures,optically active forms and pharmaceutically active derivatives thereof,wherein Y₁, and Y₂ are independently selected from N or CR₇; R₇ isselected from hydrogen, halogen, cyano, C₁₋₄ alkoxy, C₁₋₄ haloalkyl,C₁₋₄ haloalkoxy, or C₁₋₄ alkyl; Z₁ is selected from O, S, NH, or CH₂;and R₈ is selected from hydrogen, hydroxyl, C₁₋₆ alkyl, or fluorine.

According to an embodiment, the present disclosure relates to a compoundof Formula (B) or its stereoisomers, pharmaceutically acceptable salts,complexes, hydrates, solvates, tautomers, polymorphs, racemic mixtures,optically active forms and pharmaceutically active derivatives thereof,wherein Y₁, and Y₂ are independently selected from N or CR₇; R₇ isselected from hydrogen, halogen, cyano, C₁₋₄ alkoxy, or C₁₋₄ alkyl; Z₁is selected from O, or S; and R₈ is selected from hydrogen, hydroxyl,C₁₋₄ alkyl, or fluorine.

According to an embodiment, the present disclosure relates to a compoundof Formula (B) or its stereoisomers, pharmaceutically acceptable salts,complexes, hydrates, solvates, tautomers, polymorphs, racemic mixtures,optically active forms and pharmaceutically active derivatives thereof,which is selected from a group consisting of:

-   (S)-6-(5-(aminomethyl)-2-oxooxazolidin-3-yl)-2H-pyrazino[2,3-b][1,4]oxazin-3(4H)-one    (Intermediate V)

-   (R)-6-(5-(aminomethyl)-2-oxooxazolidin-3-yl)-2H-pyrazino[2,3-b][1,4]oxazin-3(4H)-one    (Intermediate VI)

-   (S)-5-(aminomethyl)-3-(3-oxo-3,4-dihydro-2H-pyrazino[2,3-b][1,4]thiazin-6-yl)oxazolidin-2-one    (Intermediate VII).

According to an embodiment, the present disclosure relates to a processof preparation of compounds of Formula (B), or its stereoisomers,pharmaceutically acceptable salts, complexes, hydrates, solvates,tautomers, polymorphs, racemic mixtures, optically active forms andpharmaceutically active derivatives thereof, said process comprising:(a) reacting a compound of Formula (C), and a compound of Formula (D) inthe presence of at least one catalyst and at least one solvent to obtaina compound of Formula (E); (b) reacting the compound of Formula (E) andat least one nitrogen compound to obtain a compound of Formula (F); and(c) reducing the compound of Formula (F) to obtain a compound Formula(B).

According to an embodiment, the present disclosure relates to a processof preparation of compounds of Formula (B) as described herein, whereinthe at least one catalyst is selected from a group consisting of Pdcontaining catalyst, t-BuXPhos-Pd, Pd(OAc)₂, and combinations thereof,the at least one solvent is selected from the group consisting of THF,toluene, dioxane, and combinations thereof, the at least one nitrogencompound is NaN₃.

According to an embodiment, the present disclosure relates to a processof preparation of compounds of Formula (B) as described herein, whereinreducing the compound of Formula (F) to obtain a compound Formula (B) iscarried out in the presence of reducing agent selected from triphenylphosphine (Ph₃P)/THF—H₂O, or hydrogen and palladium carbon (H₂/Pd—C).

According to an embodiment, the present disclosure relates to a processof preparation of compounds of Formula I, or its stereoisomers,pharmaceutically acceptable salts, complexes, hydrates, solvates,tautomers, polymorphs, racemic mixtures, optically active forms andpharmaceutically active derivatives thereof, said process comprisingreacting compounds of Formula (A) and compounds of Formula (B) inpresence of at least one reducing agent and an adsorbent to obtain thecompounds of Formula I, wherein R₁ of Formula (A) is selected from C₁₋₆alkyl, C₂₋₆ alkenyl, C₃₋₆ cycloalkyl, C₁₋₆ alkylamino, C₁₋₆aminoalkylene, or 4-7 membered saturated or unsaturated carbocyclyl orheterocyclyl ring, wherein the heterocyclyl ring is optionallysubstituted with upto three heteroatoms independently selected from O, Nor S, wherein C₁₋₆ alkyl, C₂₋₆ alkenyl, C₃₋₆ cycloalkyl, C₁₋₆alkylamino, C₁₋₆ aminoalkylene, and 4-7 membered saturated orunsaturated carbocyclyl or heterocyclyl ring are optionally substitutedwith 1 to 3 groups independently selected from halogen, amino, hydroxyl,SO₃H, O—PO₃H₂, COOR₉, CONHR₉, SO₂NHR₉, methylsulfone, C₁₋₆ alkyl, C₁₋₆alkoxy, C₁₋₆ haloalkoxy, C₃₋₆ cycloalkyl, C₃₋₆ cycloalkylamino, C₃₋₆aminocycloalkyl, C₃₋₆ cycloalkylhydroxy, C₁₋₆ alkylamino, or 3-7membered saturated or unsaturated heterocyclyl ring optionallysubstituted with upto three heteroatoms independently selected from O, Nor S; R₉ is selected from hydrogen, or C₁₋₆ alkyl; R₂ is selected fromhydrogen, fluorine, chlorine, cyano, C₁₋₆ alkoxy, or hydroxyl; R₃ isselected from hydrogen, C₁ alkyl, fluorine, C₁₋₆ alkoxy, hydroxyl, oramino; X₁ is N or CR₄; R₄ is selected from hydrogen, halogen, cyano,C₁₋₆ alkoxy, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, or C₁₋₆ alkyl; X₂ is N orCR₅; R₅ is selected from hydrogen, halogen, cyano, C₁₋₆ alkoxy, C₁₋₆haloalkyl, C₁₋₆ haloalkoxy, or C₁ alkyl; X₃ is N or CR₆; and X₄ is CR₆or C₁₋₆ alkyl when dotted line (----) represents a bond; R₆ is selectedfrom hydrogen, cyano, C₁₋₆ alkyl, C₁₋₆ alkylamino, C₁₋₆ alkoxy, C₁₋₆haloalkoxy, or COOH; or X₃ is CH₂ or O; and X₄ is CH₂ when dotted line(----) represents no bond; and n₁ is 0 to 2; R₈ of Formula (B) isselected from hydrogen, hydroxyl, C₁₋₆ alkyl, or fluorine; Y₁, and Y₂are independently selected from N or CR₇; R₇ is selected from hydrogen,halogen, cyano, C₁₋₆ alkoxy, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, or C₁₋₆alkyl; Z₁ is selected from O, S, NH, or CH₂; and R₁ of Formula I isselected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₃₋₆ cycloalkyl, C₁₋₆alkylamino, C₁₋₆ aminoalkylene, or 4-7 membered saturated orunsaturated, carbocyclyl or heterocyclyl ring, wherein the heterocyclylring is optionally substituted with upto three heteroatoms independentlyselected from O, N or S, wherein C₁₋₆ alkyl, C₂₋₆ alkenyl, C₃₋₆cycloalkyl, C₁₋₆ alkylamino, C₁₋₆ aminoalkylene, and 4-7 memberedsaturated or unsaturated carbocyclyl or heterocyclyl ring are optionallysubstituted with 1 to 3 groups independently selected from halogen,amino, hydroxyl, SO₃H, O—PO₃H₂, COOR₉, CONHR₉, SO₂NHR₉, methylsulfone,C₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₆ haloalkoxy, C₃₋₆ cycloalkyl, C₃₋₆cycloalkylamino, C₃₋₆ aminocycloalkyl, C₃₋₆ cycloalkylhydroxy, C₁₋₆alkylamino, di(C₁₋₆ alkyl)amino, or 3-7 membered saturated orunsaturated heterocyclyl ring optionally substituted with upto threeheteroatoms independently selected from O, N or S; R₉ is selected fromhydrogen, or C₁₋₆ alkyl; R₂ is selected from hydrogen, fluorine,chlorine, cyano, C₁₋₆ alkoxy, or hydroxyl; R₃ is selected from hydrogen,C₁₋₆ alkyl, fluorine, C₁₋₆ alkoxy, hydroxyl, or amino; X₁ is N or CR₄;R₄ is selected from hydrogen, halogen, cyano, C₁₋₆ alkoxy, C₁₋₆haloalkyl, C₁₋₆ haloalkoxy, or C₁₋₆ alkyl; X₂ is N or CR₅; R₅ isselected from hydrogen, halogen, cyano, C₁₋₆ alkoxy, C₁₋₆ haloalkyl,C₁₋₆ haloalkoxy, or C₁₋₆ alkyl; X₃ is N or CR₆; and X₄ is CR₆ whendotted line (----) represents a bond; R₆ is selected from hydrogen,cyano, C₁₋₆ alkyl, C₁₋₆ alkylamino, C₁₋₆ alkoxy, C₁₋₆ haloalkoxy, orCOOH, wherein C₁₋₆ alkyl, and C₁₋₆ alkylamino are optionally substitutedwith one or more groups selected from COOH, hydroxyl, amino, or C₁₋₆alkyl; or X₃ is CH₂ or O; and X₄ is CH₂ when dotted line (----)represents no bond; n₁ is 0 to 2; Y₁, and Y₂ are independently selectedfrom N or CR₇; R₇ is selected from hydrogen, halogen, cyano, C₁₋₆alkoxy, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, or C₁₋₆ alkyl; Z₁ is selectedfrom O, S, NH, or CH₂; and R₈ is selected from hydrogen, hydroxyl, C₁₋₆alkyl, or fluorine.

According to an embodiment, the present disclosure relates to a processof preparation of compounds of Formula I as described herein, whereinsaid process comprises a compound of Formula (A)

R₁ of Formula (A) is selected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₃₋₆cycloalkyl, C₁₋₆ alkylamino, C₁₋₆ aminoalkylene, or 4-7 memberedsaturated or unsaturated carbocyclyl or heterocyclyl ring, wherein theheterocyclyl ring is optionally substituted with upto three heteroatomsindependently selected from O, N or S, wherein C₁₋₆ alkyl, C₂₋₆ alkenyl,C₃₋₆ cycloalkyl, C₁₋₆ alkylamino, C₁₋₆ aminoalkylene, and 4-7 memberedsaturated or unsaturated carbocyclyl or heterocyclyl ring are optionallysubstituted with 1 to 3 groups independently selected from halogen,amino, hydroxyl, SO₃H, O—PO₃H₂, COOR₉, CONHR₉, SO₂NHR₉, methylsulfone,C₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₆ haloalkoxy, C₃₋₆ cycloalkyl, C₃₋₆cycloalkylamino, C₃₋₆ aminocycloalkyl, C₃₋₆ cycloalkylhydroxy, C₁₋₆alkylamino, di(C₁₋₆ alkyl)amino, or 3-7 membered saturated orunsaturated heterocyclyl ring optionally substituted with upto threeheteroatoms independently selected from O, N or S; R₉ is selected fromhydrogen, or C₁₋₆ alkyl; R₂ is selected from hydrogen, fluorine,chlorine, cyano, C₁₋₆ alkoxy, and hydroxyl; R₃ is selected fromhydrogen, C₁₋₆ alkyl, fluorine, C₁₋₆ alkoxy, hydroxyl, or amino; X₁ is Nor CR₄; R₄ is selected from hydrogen, halogen, cyano, C₁₋₆ alkoxy, C₁₋₆haloalkyl, C₁₋₆ haloalkoxy, or C₁₋₆ alkyl; X₂ is N or CR₅; R₅ isselected from hydrogen, halogen, cyano, C₁₋₆ alkoxy, C₁₋₆ haloalkyl,C₁₋₆ haloalkoxy, or C₁₋₆ alkyl; X₃ is N or CR₆; and X₄ is CR₆ whendotted line (----) represents a bond; R₆ is selected from hydrogen,cyano, C₁₋₆ alkyl, C₁₋₆ alkylamino, C₁₋₆ alkoxy, C₁₋₆ haloalkoxy, orCOOH; or X₃ is CH₂ or O; and X₄ is CH₂ when dotted line (----)represents no bond; and n₁ is 0 to 2.

According to an embodiment, the present disclosure relates to a processof preparation of compounds of Formula I as described herein, whereinsaid process comprises a compound of Formula (B)

wherein R₈ of Formula (B) is selected from hydrogen, hydroxyl, C₁₋₆alkyl, or fluorine; Y₁, and Y₂ are independently selected from N or CR₇;R₇ is selected from hydrogen, halogen, cyano, C₁₋₆ alkoxy, C₁₋₆haloalkyl, C₁₋₆ haloalkoxy, or C₁₋₆ alkyl; Z₁ is selected from O, S, NH,or CH₂.

According to an embodiment, the present disclosure relates to a processof preparation of compounds of Formula I as described herein, whereinthe at least one reducing agent is selected from the group consisting ofsodium borohydride, sodium cyano borohydride, sodium triacetoxyborohydride, and combinations thereof.

According to an embodiment, the present disclosure relates to a processof preparation of compounds of Formula I as described herein, whereinthe adsorbent is selected from the group consisting of molecular sieves,silica gel, zeolites, anhydrous sodium sulphate, anhydrous magnesiumsulphate, activated charcoal, and combinations thereof.

According to an embodiment, the present disclosure relates to a compoundof Formula I, or Formula (B), or its stereoisomers, pharmaceuticallyacceptable salts, complexes, hydrates, solvates, tautomers, polymorphs,racemic mixtures, optically active forms and pharmaceutically activederivatives thereof, for use as a medicament.

According to an embodiment, the present disclosure relates to a compoundof Formula I, or Formula (B), or its stereoisomers, pharmaceuticallyacceptable salts, complexes, hydrates, solvates, tautomers, polymorphs,racemic mixtures, optically active forms and pharmaceutically activederivatives thereof, for use in the preparation of medicaments forinhibiting microbial growth.

According to an embodiment, the present disclosure relates to a compoundof Formula I, or Formula (B), or its stereoisomers, pharmaceuticallyacceptable salts, complexes, hydrates, solvates, tautomers, polymorphs,racemic mixtures, optically active forms and pharmaceutically activederivatives thereof, for use in killing or inhibiting the growth of amicroorganism selected from the group consisting of Gram-positive andGram-negative bacteria.

According to an embodiment, the present disclosure relates to a compoundof Formula I, or Formula (B), or its stereoisomers, pharmaceuticallyacceptable salts, complexes, hydrates, solvates, tautomers, polymorphs,racemic mixtures, optically active forms and pharmaceutically activederivatives thereof, for use in killing or inhibiting the growth ofGram-positive and Gram-negative bacteria.

According to an embodiment, the present disclosure relates to a compoundof Formula I, or Formula (B), or its stereoisomers, pharmaceuticallyacceptable salts, complexes, hydrates, solvates, tautomers, polymorphs,racemic mixtures, optically active forms and pharmaceutically activederivatives thereof, for use in treatment of a bacterial infectioncaused by a Gram-positive bacterium or a Gram-negative bacterium.

According to an embodiment, the present disclosure relates to a compoundof Formula I, or Formula (B), or its stereoisomers, pharmaceuticallyacceptable salts, complexes, hydrates, solvates, tautomers, polymorphs,racemic mixtures, optically active forms and pharmaceutically activederivatives thereof, for use in treating a disease or condition in apatient wherein said disease or condition is caused by a microorganismselected from the group consisting of Gram-positive, and Gram-negativepathogens.

According to an embodiment, the present disclosure relates to a compoundof Formula I, or Formula (B), or its stereoisomers, pharmaceuticallyacceptable salts, complexes, hydrates, solvates, tautomers, polymorphs,racemic mixtures, optically active forms and pharmaceutically activederivatives thereof, for use in treating a disease or condition in apatient wherein said disease or condition is caused by a microorganismselected from the group consisting of Gram-positive, and Gram-negativepathogens. The patient is typically a mammal, preferably a human.

According to an embodiment, the present disclosure relates to a methodof treating a disease or condition in a patient, said method comprisingadministering to a patient a compound of Formula I, or Formula (B), orits stereoisomers, pharmaceutically acceptable salts, complexes,hydrates, solvates, tautomers, polymorphs, racemic mixtures, opticallyactive forms and pharmaceutically active derivatives thereof, whereinsaid disease or condition is caused by a microorganism selected from thegroup consisting of Gram-positive, and Gram-negative pathogens.

According to an embodiment, the present disclosure relates tomedicaments that include a compound of Formula I, or Formula (B), or anaddition salt of the compound of Formula I or Formula (B), with apharmaceutically acceptable acid or base. These medicaments find theiruse in therapeutics, especially in the treatment of bacterial infectioncaused by both drug sensitive and drug resistance bacterium includingquinolone resistance belonging to Gram positive and Gram-negativespecies; especially of those caused by Escherichia coli, Pseudomonasaurigenosa, Klebsiella pneumoniae, Acinetobacter baumannii, Enterobactercloacae, Staphylococcus aureus, Enterococcus faecalis Enterococcusfaecium, Legionella pneumophila. Mycoplasma pneumonia, Acinetobacterhaemolyticus, Acinetobacter junii, Acinetobacter lwoffi, Burkholderiacepacia, Chlamydophila pneumoniae, Clostridium difficili, Enterobacteraerogenes, Enterobacter cloacae, Moraxella catarrhalis, Neisseriagonorrhoeae, Neisseria meningitides, Proteus mirabilis, Proteus houseri,Citrobacter freundii, Citrobacter kosari, Citrobacter barakii, Seratiamarcescens, Klebsiella oxytoca, Morganella morganii, Helicobacterpyroli, Mycobacterium tuberculosis.

According to an embodiment, the present disclosure relates to the use ofa compound of Formula I, or Formula (B), or its stereoisomers,pharmaceutically acceptable salts, complexes, hydrates, solvates,tautomers, polymorphs, racemic mixtures, optically active forms, andpharmaceutically active derivative thereof, in the manufacture of amedicament for the treatment of an infection caused by bacterial speciesin a warm-blooded animal, wherein the warm-blooded animal is man.

According to an embodiment, the present disclosure relates to the use ofa compound of Formula I, or Formula (B), or its stereoisomers,pharmaceutically acceptable salts, complexes, hydrates, solvates,tautomers, polymorphs, racemic mixtures, optically active forms andpharmaceutically active derivative thereof, in the manufacture of amedicament for the production of an antibacterial effect in awarm-blooded animal, wherein the warm-blooded animal is man.

According to an embodiment, the present disclosure relates to apharmaceutical composition comprising a compound of Formula I, orFormula (B), or its stereoisomers, pharmaceutically acceptable salts,complexes, hydrates, solvates, tautomers, polymorphs, racemic mixtures,optically active forms and pharmaceutically active derivative thereoftogether with a pharmaceutically acceptable carrier.

According to an embodiment, the present disclosure relates to apharmaceutical composition comprising a compound of Formula I, orFormula (B), or its stereoisomers, pharmaceutically acceptable salts,complexes, hydrates, solvates, tautomers, polymorphs, racemic mixtures,optically active forms and pharmaceutically active derivative thereoftogether with a pharmaceutically acceptable carrier, and in combinationwith at least one antibiotic.

According to an embodiment, the present disclosure relates to use of acompound of Formula I, or Formula (B), or its stereoisomers,pharmaceutically acceptable salts, complexes, hydrates, solvates,tautomers, polymorphs, racemic mixtures, optically active forms andpharmaceutically active derivatives thereof, in killing or inhibitingthe growth of a microorganism selected from the group consisting ofbacteria, virus, fungi, and protozoa.

According to an embodiment, the present disclosure relates to a methodfor treating a bacterial infection caused by bacterial species in awarm-blooded animal such as man, said method including administering tosaid animal an effective amount of a compound of Formula I, or Formula(B), or a pharmaceutically acceptable salt thereof.

According to an embodiment, the present disclosure relates to a methodfor producing an antibacterial effect in a warm-blooded animal such asman, said method including administering to said animal an effectiveamount of a compound of Formula I, or Formula (B), or a pharmaceuticallyacceptable salt thereof.

According to an embodiment, the present disclosure relates to a compoundof Formula I, or a pharmaceutically acceptable salt thereof, for use inthe treatment and/or prophylaxis of bacterial infections in awarm-blooded animal, wherein the warm-blooded animal is man.

According to an embodiment, the present disclosure relates to a compoundof Formula I, or Formula (B), or a pharmaceutically acceptable saltthereof, for the therapeutic and prophylactic treatment of mammalsincluding humans, in particular in treating bacterial infections causedby bacterial species, is normally formulated in accordance with standardpharmaceutical practice as a pharmaceutical composition.

According to an embodiment, the present disclosure relates to apharmaceutical composition including a compound of Formula I, or Formula(B), or its stereoisomers, pharmaceutically acceptable salts, complexes,hydrates, solvates, tautomers, polymorphs, racemic mixtures, opticallyactive forms and pharmaceutically active derivative thereof, and atleast one pharmaceutically acceptable carrier, diluent, or excipient.

According to an embodiment, the present disclosure relates to the use ofa pharmaceutical composition including a compound of Formula I, orFormula (B), or its stereoisomers, pharmaceutically acceptable salts,complexes, hydrates, solvates, tautomers, polymorphs, racemic mixtures,optically active forms and pharmaceutically active derivative thereof,in the manufacture of a medicament for the treatment of a bacterialinfection caused by bacterial species in a warm-blooded animal, whereinthe warm-blooded animal is man.

According to an embodiment, the present disclosure relates to the use ofa pharmaceutical composition including a compound of Formula I, orFormula (B), or its stereoisomers, pharmaceutically acceptable salts,complexes, hydrates, solvates, tautomers, polymorphs, racemic mixtures,optically active forms and pharmaceutically active derivative thereof,in the manufacture of a medicament for the production of anantibacterial effect in a warm-blooded animal, wherein the warm-bloodedanimal is man.

According to an embodiment, the present disclosure relates to a methodfor treatment of bacterial infection in a subject, said method includingadministering to said subject an effective amount of a pharmaceuticalcomposition including a compound of Formula I, or Formula (B), or itsstereoisomers, pharmaceutically acceptable salts, complexes, hydrates,solvates, tautomers, polymorphs, racemic mixtures, optically activeforms and pharmaceutically active derivative thereof.

According to an embodiment, the present disclosure relates to a compoundof Formula I, or Formula (B), as described herein, wherein the bacterialinfection is caused by a Gram-positive or a Gram-negative pathogen.

According to an embodiment, the present disclosure relates to a compoundof Formula I, or Formula (B), as described herein, wherein the bacterialinfection is caused by Escherichia coli, Pseudomonas aurigenosa,Klebsiella pneumoniae, Acinetobacter baumannii, Enterobacter cloacae,Staphylococcus aureus, Enterococcus faecalis Enterococcus faecium,Legionella pneumophila. Mycoplasma pneumonia, Acinetobacterhaemolyticus, Acinetobacter junii, Acinetobacter lwoffi, Burkholderiacepacia, Chlamydophila pneumoniae, Clostridium difficili, Enterobacteraerogenes, Enterobacter cloacae, Moraxella catarrhalis, Neisseriagonorrhoeae, Neisseria meningitides, Proteus mirabilis, Proteus houseri,Citrobacter freundii, Citrobacter kosari, Citrobacter barakii, Seratiamarcescens, Klebsiella oxytoca, Morganella morganii, Helicobacterpyroli, Mycobacterium tuberculosis.

According to an embodiment, the present disclosure relates to a methodfor treating infection caused by bacterial species in a warm-bloodedanimal, wherein the warm-blooded animal is man, said method includingadministering to said animal an effective amount of a pharmaceuticalcomposition including a compound of Formula I, or Formula (B), or itsstereoisomers, pharmaceutically acceptable salts, complexes, hydrates,solvates, tautomers, polymorphs, racemic mixtures, optically activeforms and pharmaceutically active derivative thereof.

According to an embodiment, the present disclosure relates to a methodfor producing an antibacterial effect in a warm-blooded animal such asman, said method including administering to said animal an effectiveamount of a pharmaceutical composition including a compound of FormulaI, or Formula (B), or its stereoisomers, pharmaceutically acceptablesalts, complexes, hydrates, solvates, tautomers, polymorphs, racemicmixtures, optically active forms and pharmaceutically active derivativethereof.

According to an embodiment, the present disclosure relates to apharmaceutical composition comprising a compound of Formula I, orFormula (B), or its stereoisomers, pharmaceutically acceptable salts,complexes, hydrates, solvates, tautomers, polymorphs, racemic mixtures,optically active forms and pharmaceutically active derivative thereof,together with a pharmaceutically acceptable carrier, optionally incombination with one or more other pharmaceutical compositions.

According to an embodiment, the present disclosure relates to apharmaceutical composition comprising a compound of Formula I, orFormula (B), or its stereoisomers, pharmaceutically acceptable salts,complexes, hydrates, solvates, tautomers, polymorphs, racemic mixtures,optically active forms and pharmaceutically active derivative thereof,and a pharmaceutically acceptable diluent or carrier.

According to an embodiment, the present disclosure relates to acomposition comprising a compound of Formula I, or Formula (B), or itsstereoisomers, pharmaceutically acceptable salts, complexes, hydrates,solvates, tautomers, polymorphs, racemic mixtures, optically activeforms and pharmaceutically active derivative thereof, and a carrier.

The language “pharmaceutically acceptable” includes compounds,materials, compositions, and/or dosage forms which are, within the scopeof sound medical judgment, suitable for use in contact with the tissuesof human beings and animals without excessive toxicity, irritation,allergic response, or other problem or complication, commensurate with areasonable benefit/risk ratio.

The compounds of Formula I or Formula (B) may form stablepharmaceutically acceptable acid or base salts, and in such casesadministration of a compound as a salt may be appropriate. Examples ofacid addition salts include acetate, adipate, ascorbate, benzoate,benzenesulfonate, bicarbonate, bisulfate, butyrate, camphorate,camphorsulfonate, choline, citrate, cyclohexyl sulfamate,diethylenediamine, ethanesulfonate, fumarate, glutamate, glycolate,hemisulfate, 2-hydroxyethylsulfonate, heptanoate, hexanoate,hydrochloride, hydrobromide, hydroiodide, hydroxymaleate, lactate,malate, maleate, methanesulfonate, meglumine, 2-naphthalenesulfonate,nitrate, oxalate, pamoate, persulfate, phenylacetate, phosphate,diphosphate, picrate, pivalate, propionate, quinate, salicylate,stearate, succinate, sulfamate, sulfanilate, sulfate, tartrate, tosylate(p-toluenesulfonate), trifluoroacetate, and undecanoate. Examples ofbase salts include ammonium salts; alkali metal salts such as sodium,lithium and potassium salts; alkaline earth metal salts such asaluminum, calcium and magnesium salts; salts with organic bases such asdicyclohexylamine salts and N10 methyl-D-glucamine; and salts with aminoacids such as arginine, lysine, ornithine, and so forth. Also, basicnitrogen-containing groups may be quaternized with such agents as: loweralkyl halides, such as methyl, ethyl, propyl, and butyl halides; dialkylsulfates such as dimethyl, diethyl, dibutyl; diamyl sulfates; long chainhalides such as decyl, lauryl, myristyl and stearyl halides; arylalkylhalides such as benzyl bromide and others. Non-toxic physiologicallyacceptable salts are preferred, although other salts may be useful, suchas in isolating or purifying the product.

The salts may be formed by conventional means, such as by reacting thefree base form of the product with one or more equivalents of theappropriate acid in a solvent or medium in which the salt is insoluble,or in a solvent such as water, which is removed in vacuo or by freezedrying or by exchanging the anions of an existing salt for another anionon a suitable ion-exchange resin.

The compositions of the disclosure may be in a form suitable for oraluse (for example as tablets, lozenges, hard or soft capsules, aqueous oroily suspensions, emulsions, dispersible powders or granules, syrups orelixirs), for topical use (for example as creams, ointments, gels, oraqueous or oily solutions or suspensions), for administration byinhalation (for example as a finely divided powder or a liquid aerosol),for administration by insufflation (for example as a finely dividedpowder) or for parenteral administration (for example as a sterileaqueous or oily solution for intravenous, subcutaneous, intramuscular orintramuscular dosing or as a suppository for rectal dosing).

The present disclosure relates to a process of preparation of acomposition comprising a compound of Formula I, or Formula (B), or itsstereoisomers, pharmaceutically acceptable salts, complexes, hydrates,solvates, tautomers, polymorphs, racemic mixtures, optically activeforms and pharmaceutically active derivative thereof together with acarrier.

The present disclosure relates to a process of preparation ofpharmaceutical composition comprising a compound of Formula I, orFormula (B), or its stereoisomers, pharmaceutically acceptable salts,complexes, hydrates, solvates, tautomers, polymorphs, racemic mixtures,optically active forms and pharmaceutically active derivative thereof,together with a pharmaceutically acceptable carrier, optionally incombination with one or more other pharmaceutical compositions.

The compositions of the present disclosure may be obtained byconventional procedures using conventional pharmaceutical excipientswell known in the art. Thus, compositions intended for oral use maycontain, for example, one or more colouring, sweetening, flavouringand/or preservative agents

Suitable pharmaceutically acceptable excipients for a tablet formulationinclude, for example, inert diluents such as lactose, sodium carbonate,calcium phosphate or calcium carbonate; granulating and disintegratingagents such as corn starch or algenic acid; binding agents such asstarch; lubricating agents such as magnesium stearate, stearic acid ortalc; preservative agents such as ethyl or propyl p-hydroxybenzoate; andanti-oxidants, such as ascorbic acid. Tablet formulations may beuncoated or coated either to modify their disintegration and thesubsequent absorption of the active ingredient within thegastrointestinal tract, or to improve their stability and/or appearance,in either case, using conventional coating agents or procedures wellknown in the art.

Compositions for oral use may be in the form of hard gelatin capsules inwhich the active ingredient is mixed with an inert solid diluent, forexample, calcium carbonate, calcium phosphate or kaolin, or as softgelatin capsules in which the active ingredient is mixed with water oroil such as peanut oil, liquid paraffin, or olive oil.

Aqueous suspensions generally contain the active ingredient in finelypowdered form or in the form of nano or micronized particles togetherwith one or more suspending agents, such as sodiumcarboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose,sodium alginate, polyvinyl-pyrrolidone, gum tragacanth and gum acacia;dispersing or wetting agents such as lecithin or condensation productsof an alkylene oxide with fatty acids (for example polyoxethylenestearate), or condensation products of ethylene oxide with long chainaliphatic alcohols, for example heptadecaethyleneoxycetanol, orcondensation products of ethylene oxide with partial esters derived fromfatty acids and a hexitol such as polyoxyethylene sorbitol monooleate,or condensation products of ethylene oxide with long chain aliphaticalcohols, for example heptadecaethyleneoxycetanol, or condensationproducts of ethylene oxide with partial esters derived from fatty acidsand a hexitol such as polyoxyethylene sorbitol monooleate, orcondensation products of ethylene oxide with partial esters derived fromfatty acids and hexitol anhydrides, for example polyethylene sorbitanmonooleate. The aqueous suspensions may also contain one or morepreservatives such as ethyl or propyl p-hydroxybenzoate; anti-oxidantssuch as ascorbic acid); coloring agents; flavoring agents; and/orsweetening agents such as sucrose, saccharine or aspartame.

Oily suspensions may be formulated by suspending the active ingredientin a vegetable oil such as arachis oil, olive oil, sesame oil or coconutoil or in a mineral oil such as liquid paraffin. The oily suspensionsmay also contain a thickening agent such as beeswax, hard paraffin orcetyl alcohol. Sweetening agents such as those set out above, andflavoring agents may be added to provide a palatable oral preparation.These compositions may be preserved by the addition of an anti-oxidant,wherein the anti-oxidant comprises ascorbic acid.

Dispersible powders and granules suitable for preparation of an aqueoussuspension by the addition of water generally contain the activeingredient together with a dispersing or wetting agent, suspending agentand one or more preservatives. Suitable dispersing or wetting agents andsuspending agents are exemplified by those already mentioned above.Additional excipients such as sweetening, flavoring and coloring agents,may also be present.

The pharmaceutical compositions of the disclosure may also be in theform of oil-in-water emulsions. The oily phase may be a vegetable oil,such as olive oil or arachis oil, or a mineral oil, such as for exampleliquid paraffin or a mixture of any of these. Suitable emulsifyingagents may be, for example, naturally-occurring gums such as gum acaciaor gum tragacanth, naturally-occurring phosphatides such as soya bean,lecithin, an esters or partial esters derived from fatty acids andhexitol anhydrides (for example sorbitan monooleate) and condensationproducts of the said partial esters with ethylene oxide such aspolyoxyethylene sorbitan monooleate. The emulsions may also containsweetening, flavoring and preservative agents.

Syrups and elixirs may be formulated with sweetening agents such asglycerol, propylene glycol, sorbitol, aspartame or sucrose, and may alsocontain a demulcent, preservative, flavoring and/or coloring agent.

The pharmaceutical compositions may also be in the form of a sterileinjectable aqueous or oily suspension, which may be formulated accordingto known procedures using one or more of the appropriate dispersing orwetting agents and suspending agents, which have been mentioned above. Asterile injectable preparation may also be a sterile injectable solutionor suspension in a non-toxic parenterally-acceptable diluent or solvent,for example a solution in 1,3-butanediol.

Compositions for administration by inhalation may be in the form of aconventional pressurized aerosol arranged to dispense the activeingredient either as an aerosol containing finely divided solid orliquid droplets. Conventional aerosol propellants such as volatilefluorinated hydrocarbons or hydrocarbons may be used and the aerosoldevice is conveniently arranged to dispense a metered quantity of activeingredient.

Compositions for administration may also be formulated as a liposomepreparation. The liposome preparation can comprise liposomes whichpenetrate the cells of interest or stratum corneum, and fuse with thecell membrane, resulting in delivery of the contents of the liposomeinto the cell. Other suitable formulations can employ niosomes. Niosomesare lipid vesicles similar to liposomes, with membrane consistinglargely of nonionic lipids, some forms of which are effective fortransporting compounds across the stratum corneum.

Compositions for administration may also be formulated as a depotpreparation, which may be administered by implantation or byintramuscular injection. The compositions may be formulated withsuitable polymeric or hydrophobic material (as an emulsion in acceptableoil), ion exchange resins, or sparingly soluble derivatives.

The compound of the present disclosure can also be administered insustained release forms or from sustained release drug delivery systems.

For further information on formulation, drug delivery as well asprocessing techniques the reader is referred to Remington'sPharmaceutical Sciences (21^(st) Edition, 2005, University of thesciences in Philadelphia, Lippincott William & Wilkins)

The amount of active ingredient that is combined with one or moreexcipients to produce a single dosage form will necessarily varydepending upon the host treated and the particular route ofadministration. For example, a formulation intended for oraladministration to humans will generally contain, for example, from 0.5mg to 4 g of active agent compounded with an appropriate and convenientamount of excipients which may vary from about 5 to about 98 percent byweight of the total composition. Dosage unit forms will generallycontain about 1 mg to about 500 mg of an active ingredient. For furtherinformation on Routes of Administration and Dosage Regimes the reader isreferred to Chapter 25.3 in Volume 5 of Comprehensive MedicinalChemistry (Corwin Hansch; Chairman of Editorial Board), Pergamon Press1990 and Remington's Pharmaceutical Sciences (21^(st) Edition, 2005,University of the sciences in Philadelphia, Lippincott William &Wilkins).

As stated above the size of the dose required for the therapeutic orprophylactic treatment of a particular disease state will necessarily bevaried depending on the host treated, the route of administration andthe severity of the illness being treated. Preferably a daily dose inthe range of 1-25 mg/kg is employed. Accordingly, the optimum dosage maybe determined by the practitioner who is treating any particularpatient.

In any of the pharmaceutical compositions, processes, methods, uses,medicaments, and manufacturing features mentioned herein, any of thealternate aspects of the compounds of the disclosure described hereinalso apply.

The compounds disclosed herein may be applied as a sole therapy or mayinvolve, in addition to a compound of the disclosure, one or more othersubstances and/or treatments. Such conjoint treatment may be achieved byway of the simultaneous, sequential or separate administration of theindividual components of the treatment. Where the administration issequential or separate, the delay in administering the second componentshould not be such as to lose the beneficial effect of the combination.Suitable classes and substances may be selected from one or more of thefollowing: i) other antibacterial agents for example macrolides e.g.erythromycin, azithromycin or clarithromycin; quinolones e.g.ciprofloxacin or levofloxacin; B lactams e.g. penicillins e.g.amoxicillin or piperacillin; cephalosporins e.g. ceftriaxone orceftazidime; carbapenems, e.g. meropenem or imipenem etc;aminoglycosides e.g. gentamicin or tobramycin; or oxazolidinones; and/orii) anti-infective agents for example, an antifungal triazole e.g. oramphotericin; and/or iii) biological protein therapeutics for exampleantibodies, cytokines, bactericidal/permeability increasing protein(BPI) products; and/or iv) one or more antibacterial agents useful inthe treatment of Mycobacterium tuberculosis such as one or more ofrifampicin, isoniazid, pyrizinamide, ethambutol, quinolones e.g.moxifloxacin or gatifloxacin, streptomycin and/or v) efflux pumpinhibitors.

According to an embodiment, the present disclosure relates to a compoundof the Formula I, or Formula (B), or a pharmaceutically acceptable saltthereof and a chemotherapeutic agent selected from: i) one or moreadditional antibacterial agents; and/or ii) one or more anti-infectiveagents; and/or iii) biological protein therapeutics for exampleantibodies, cytokines, bactericidal/permeability increasing protein(BPI) products; iv) one or more antibacterial agents useful in thetreatment of pulmonary tuberculosis, extra-pulmonary tuberculosis, aviuminfections, buruli ulcers and/or v) one or more efflux pump inhibitors.

If not commercially available, the necessary starting materials for theprocedures such as those described herein may be made by procedureswhich are selected from standard organic chemical techniques, techniqueswhich are analogous to the synthesis of known, structurally similarcompounds, or techniques which are analogous to the described procedureor the procedures described in the Examples.

It is noted that many of the starting materials for synthetic methods asdescribed herein are commercially available and/or widely reported inthe scientific literature or could be made from commercially availablecompounds using adaptations of processes reported in the scientificliterature. The reader is further referred to Advanced OrganicChemistry, 5th Edition, by Jerry March and Michael Smith, published byJohn Wiley & Sons 2001, for general guidance on reaction conditions andreagents.

It will also be appreciated that in some of the reactions mentionedherein it may be necessary/desirable to protect any sensitive groups incompounds. The instances where protection is necessary or desirable areknown to those skilled in the art, as are suitable methods for suchprotection. Conventional protecting groups may be used in accordancewith standard practice (for illustration see T. W. Greene, ProtectiveGroups in Organic Synthesis, published by John Wiley and Sons, 1991) andas described hereinabove.

EXAMPLES Abbreviations

APCI—atmospheric pressure chemical ionization;

ATP—adenosine triphosphate;

BSA—bovine serum albumin;

CDCl₃—deuterated chloroform;

CLSI—Clinical and Laboratory Standards Institute;

DCM—dichloromethane;

DMAP—4-dimethylaminopyridine;

DMF—dimethylformamide;

DMSO—dimethylsulfoxide;

DTT—dithiothretol;

EtOAc—ethyl acetate;

EDTA—ethylenediamine tetra acetic acid;

HPLC—high pressure liquid chromatography;

LC/MS—liquid chromatography/mass spectrometry;

MPLC—medium pressure liquid chromatography;

MeOD—deuterated methanol, i.e. D₃COD;

MeOH— methanol;

MS—mass spectroscopy; ESP (or ES)—electrospray; EI—electron impact;

MTBD—N-methyl-1,5,7-triazabicyclo[4.4.0]dec-5-ene;

NMR—nuclear magnetic resonance spectroscopy;

OD—optical density;

SDS—sodiumdodecylsulphate;

STEB—sucrose tris EDTA buffer;

TAE—tris acetic acid EDTA buffer;

THF—tetrahydrofuran;

TFA—trifluoroacetic acid;

h—hour(s);

min—minute(s);

d—day(s);

v/v—ratio of volume/volume;

Boc—t-butoxycarbonyl;

Cbz—benzyloxycarbonyl;

Bz—benzoyl;

TLC—thin layer chromatography;

atm—atmospheric pressure;

rt—room temperature;

mg—milligram;

ng—nanogram;

g—gram;

μL—microliter;

mL—milliliter;

L—liter;

μM—micromolar;

mM—millimolar;

nm—nanometer.

GENERAL CONSIDERATIONS

If not commercially available, the necessary starting materials for theprocedures such as those described herein may be made by procedureswhich are selected from standard organic chemical techniques, techniqueswhich are analogous to the synthesis of known, structurally similarcompounds, or techniques which are analogous to the described procedureor the procedures described in the Examples.

It is noted that many of the starting materials for synthetic methods asdescribed herein are commercially available and/or widely reported inthe scientific literature or could be made from commercially availablecompounds using adaptations of processes reported in the scientificliterature. The reader is further referred to Advanced OrganicChemistry, 5^(th) Edition, by Jerry March and Michael Smith, publishedby John Wiley & Sons 2001, for general guidance on reaction conditionsand reagents.

It will also be appreciated that in some of the reactions mentionedherein it may be necessary/desirable to protect any sensitive groups incompounds. The instances where protection is necessary or desirable areknown to those skilled in the art, as are suitable methods for suchprotection. Conventional protecting groups may be used in accordancewith standard practice (for illustration see T. W. Greene, ProtectiveGroups in Organic Synthesis, published by John Wiley and Sons, 1991) andas described hereinabove.

The following examples provide the details about the synthesis,activities and applications of the compounds of the present disclosure.It should be understood the following is representative only, and thatthe invention is not limited by the details set forth in these examples.

Material and Methods

Evaporations were carried out by rotary evaporation in vacuo and work upprocedures were carried out after removal of residual solids byfiltration; temperatures are quoted as ° C.; operations were carried outat room temperature, that is typically in the range 18 to 26° C. andwithout the exclusion of air unless otherwise stated, or unless theskilled person would otherwise work under an inert atmosphere; columnchromatography (by the flash procedure) was used to purify compounds andwas performed on Merck Kiesel gel silica (Art. 9385) unless otherwisestated; in general, the course of reactions was followed by TLC, HPLC,or LC/MS and reaction times are given for illustration only; yields aregiven for illustration only and are not necessarily the maximumattainable; the structure of the end products of the invention wasgenerally confirmed by NMR and mass spectral techniques. Proton magneticresonance spectra were generally determined in DMSO d6 unless otherwisestated, using a Bruker DRX 300 spectrometer or a Bruker DRX-400spectrometer, operating at a field strength of 300 MHz or 400 MHz,respectively. In cases where the NMR spectrum is complex, onlydiagnostic signals are reported. Chemical shifts are reported in partsper million downfield from tetramethylsilane as an external standard (*scale) and peak multiplicities are shown thus: s, singlet; d, doublet;dd, doublet of doublets; dt, doublet of triplets; dm, doublet ofmultiplets; t, triplet, m, multiplet; br, broad. Fast atom bombardment(FAB) mass spectral data were generally obtained using a Platformspectrometer (supplied by Micromass) run in electrospray and, whereappropriate, either positive ion data or negative ion data werecollected or using Agilent 1100 series LC/MS equipped with Sedex 75ELSD,and where appropriate, either positive ion data or negative ion datawere collected. The lowest mass major ion is reported for moleculeswhere isotope splitting results in multiple mass spectral peaks (forexample when chlorine is present). Reverse Phase HPLC was carried outusing YMC Pack ODS AQ (100×20 mmID, S 5 particle size, 12 nm pore size)on Agilent instruments; each intermediate was purified to the standardrequired for the subsequent stage and was characterized in sufficientdetail to confirm that the assigned structure was correct; purity wasassessed by HPLC, TLC, or NMR and identity was determined by infraredspectroscopy (IR), mass spectroscopy or NMR spectroscopy as appropriate.

Example 1

General Procedure for Synthesis of Compounds of Formula I

The present invention provides a process for preparing compounds ofFormula I, and pharmaceutically acceptable salts thereof; the processinvolves reacting a compound of Formula (A) and an amine derivative ofFormula (B) under reductive amination conditions, wherein n₁=0 or 1; R₈is H.

General Procedure to Prepare the Compounds of Formula (A)

Palladium catalysed hydroxylation of halo arenes such as Formula (D) wascarried out to obtain the compounds of Formula (C). Further thecompounds of Formula (C) were treated with haloalkyl acetal reagent (e.gBrCH₂(CH₂)n₁CH(OCH₂CH₃)₂) to obtain the compounds of Formula (A).

The compounds of Formula Ia and Formula Ib where in Z₁ is O; n₁=0; R₃ isH or OH; and R₈ is H; can be prepared by reacting compounds of Formula(E) with compounds of Formula (G) or (F) as shown Scheme 1.

Compounds of Formula (E) may be prepared from compounds of Formula (H)and compounds of Formula I as summarised in Scheme 2. Palladiumcatalysed Buchwald coupling of compounds of Formula (H) with Formula (I)under optimal reaction conditions provided the compounds of Formula (J).Further compounds of Formula (J) was converted to compounds of Formula(K) via azidation reaction and reduction of azide functionality providedthe compounds Formula (E).

Example 2 Synthesis of Intermediates Synthesis of2-((5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridin-4-yl)oxy)acetaldehyde(Intermediate I)

Step 1: Synthesis of2,2-dimethyl-2,3-dihydro-5H-[1,4,2]oxazasilino[6,5,4-de][1,5]naphthyridin-5-one(Ia)

To a stirred suspension of NaH (0.34 g, 8.5 mmol) in dry DMF was added6-Methoxy-1,5-naphthyridin-4-ol (Combi-Blocks, 1 g, 5.6 mmol) in portionwise at 0° C. The reaction mixture was allowed stir at rt for 1 h. Tothis was added chloro (chloromethyl) dimethyl) silane (1.29 g, 9.09mmol) at room temperature and the reaction mixture was heated to 100° C.for 16 h. The reaction mixture was concentrated, and the crude productwas co-evaporated with toluene to get the crude product Ta (0.5 gm) asoff white solid and the material was used as such for next step withoutfurther purification. LC-MS Calc. for C₁₁H₁₂N₂O₂Si: 232.31; Obs.:233.1[M⁺+H].

Step 2: Synthesis of 8-hydroxy-1-methyl-1,5-naphthyridin-2(1H)-one (Ib)

To a stirred solution of Ta (0.5 g, 2.15 mmol) in dry dioxane and MeOH(2:1, 16 mL) was added CsF (0.98 g, 6.46 mmol) and the resulting mixturewas heated to 80° C. for 12 h. The reaction mixture was cooled to rt andsolvent was evaporated the residue was neutralised with 1.5 N HCl. Theorganic product was extracted with EtOAc:MeOH (9:1, 50 mL) and washedwith brine solution (20 mL). The organic layer was dried over Na₂SO₄ andconcentrated to get the crude product Ib (0.3 gm) as off-white solid.The crude was used as such for the next step without furtherpurification. LC-MS Calc. for C₉H₈N₂O₂: 176.18; Obs.: 177.1 [M⁺+H]; ¹HNMR (400 MHz, DMSO-D₆): δ 7.95-7.90 (m, 2H), 6.91 (d, J=9.6 Hz, 1H),6.59 (s, 1H), 3.96 (s, 3H), 3.12 (s, 1H).

Step 3: Synthesis of 8-(2,2-diethoxyethoxy)-1-methyl-1,5-naphthyridin-2(1H)-one (Ic)

To a stirred solution of Ib (0.3 g, 17.04 mmol) in dry DMSO (6 mL) wasadded Cs₂CO₃ (0.66 g, 2.04 mmol) followed by the addition ofbromoacetaldehyde diethylacetal (0.47 g, 2.38 mmol). The resultingmixture was heated to 90° C. for 16 h. The reaction mixture was dilutedwith EtOAc (50 mL) and washed with water (2×50 mL). The organic layerwas dried over Na₂SO₄ and concentrated to get the crude product. Thecrude was purified by column chromatography on silica gel (60-120 mesh,30% EtOAc in Pet. ether) to afford Ic as yellow viscous liquid (0.2 gm).LC-MS Calc. for C₁₅H₂₀N₂O₄: 292.34; Obs.: 293.2 [M⁺+H].

Step 4: Synthesis of2-((5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridin-4-yl)oxy)acetaldehyde(I)

A solution of Ic (0.2 g, 0.68 mmol) in dichloromethane (3 mL), wascooled to 0° C., was added trifluoroacetic acid (1 mL). The reactionmixture was allowed to stir at rt for 30 min. The reaction mixture wasconcentrated, and the residue was diluted DCM (5 mL) and neutralized byusing 10% NaHCO₃ solution. The organic layer was separated, dried oversodium sulphate and concentrated to get the crude product I (0.1 gm).The crude material used was used for the synthesis of Compound 1 withoutfurther purification. LC-MS Calc. for C₁₁H₁₀N₂O₃: 218.21; Obs.: 219.1[M⁺+H].

Synthesis of2-((7-fluoro-1-methyl-2-oxo-1,2-dihydroquinolin-8-yl)oxy)acetaldehyde(Intermediate II)

Step 1: Synthesis of 7-fluoro-8-hydroxy-1-methylquinolin-2(1H)-one (IIa)

To a mixture of 8-bromo-7-fluoro-1-methylquinolin-2(1H)-one (CAS:1002108-91-9, 1 g, 3.9 mmol) in 1, 4-dioxane (20 mL) was purged N2 for10 min. To this was added Pd₂ (dba) 3 (0.071 g, 0.078 mmol) andt-Butylxphos-Pd-G3 (0.123 g, 0.156 mmol). After 5 minutes underdegasification KOH (0.43 g, 7.8 mmol) dissolved in H₂O (5 mL) was addedin to the reaction mixture. The resultant mixture stirred at 100° C. for2 hours. The reaction mixture was cooled and acidified with 1.5N diluteHCl and extracted with ethyl acetate (4×125 mL). The organic layer waswashed with brine (2×100 mL), dried over Na₂SO₄ and concentrated underreduced pressure. The crude was triturated with petroleum ether toafford pure compound IIa (0.5 gm). LC-MS Calc. for C₁₀H₈FNO₂: 193.18;Obs.: 194.2, [M⁺+H]; ¹H NMR (400 MHz, DMSO-D₆): δ 10.02 (s, 1H), 7.79(d, J=9.30 Hz, 1H), 7.11-7.14 (m, 2H), 6.52 (d, J=9.30 Hz, 1H), 3.89 (s,3H).

Step 2: Synthesis of 8-(2,2-diethoxyethoxy)-7-fluoro-1-methylquinolin-2(1H)-one (Ib)

To a mixture of Ha (0.5 g, 2.59 mmol) in DMSO (20 mL) was added Cs₂CO₃(2.52 g, 7.77 mmol) and Bromo acetaldehyde diethylacetal (0.765 g, 3.88mmol). The resultant mixture stirred at 90° C. for 12 hours. Thereaction mixture was cooled and quenched with water extracted with ethylacetate (4×125 mL). The organic layer was washed with brine (2×100 mL),dried over Na₂SO₄ and concentrated under reduced pressure. The crude waspurified by column chromatography using silica gel (230-400 mesh)eluting with 10-15% of ethyl acetate in petroleum ether to afford purecompound IIb (0.5 gm). LC-MS Calc. for C₁₆H₂₀FNO₄: 309.34; Obs.: 310.1,[M⁺+H].

Step 3: Synthesis of2-((7-fluoro-1-methyl-2-oxo-1,2-dihydroquinolin-8-yl)oxy)acetaldehyde(II)

To a mixture of IIb (0.3 g, 0.96 mmol) in (DCM 3 mL) was cooled to 0° C.was added TFA (4 mL). The reaction mixture was stirred at roomtemperature for 2 h. Reaction mixture cooled and quenched with 10%sodium bicarbonate solution extracted with DCM. The organic layer waswashed with brine (2×100 mL), dried over Na₂SO₄ and concentrated underreduced pressure. The crude was triturated with petroleum ether toafford crude II (0.2 gm) and as such used for next step without furtherpurification. 1H NMR (400 MHz, CDCl₃): δ 9.93 (s, 1H), 7.58 (d, J=9.52Hz, 1H), 7.27-7.28 (m, 1H), 6.68 (d, J=9.40 Hz, 1H), 4.66 (s, 1H), 3.98(s, 3H).

Synthesis of 6-bromo-2H-pyrido[3, 2-b][1,4]oxazin-3(4H)-one(Intermediate III)

Step 1: Synthesis of 6-bromo-2-nitropyridin-3-ol (Ia)

To a solution of 2-nitropyridin-3-ol (20 g, 0.142 mol) in DMF (400 ml),N-bromosuccinimide (32.52 g, 0.187 mol) was added portion wise over aperiod of 5 hours at 0° C. The reaction mixture was stirred for roomtemperature for 12 h. After completion of the reaction, the reactionmixture was concentrated in vacuo. The residue was taken up in the etherand the mixture was stirred for 30 min. The precipitate was removed byfiltration and the filtrate was concentrated in vacuo to get6-bromo-2-nitropyridin-3-ol, IIa (40 g, 46%) as a mixture of mono and dibromo compound. The crude LCMS showed 46% of expected mono-bromocompound, this material was used as such for next step without furtherpurification. LC-MS Calc. for C₅H₃BrN₂O₃: 218.99; Obs.: 219.2.

Step 2: Synthesis of ethyl 2-((6-bromo-2-nitropyridin-3-yl)oxy)acetate(IIIb)

To solution of 6-bromo-2-nitropyridin-3-ol, IIIa (40 g, 0.182 mol) inacetone (400 ml), cooled to 0° C., potassium carbonate (50.41 g, 0.365mol), was added and stirred for 5 min. Then, ethyl bromoacetate (39.7 g,0.237 mol) was added slowly and refluxed at 65° C. for 12 h. Aftercompletion of the reaction, it was filtered, and the filtrate wasconcentrated in vacuo. The crude was diluted with water and extractedwith ethyl acetate (2×600 mL). The combined organic layers were washedwith brine solution, dried over Na₂SO₄, filtered and concentrated invacuo. It was purified by column chromatography on silica gel withgradient elution of 20-22% of ethyl acetate in pet ether to obtain ethyl2-((6-bromo-2-nitropyridin-3-yl)oxy)acetate, IIIb (21 g, 75.32%) as apale yellow solid. LC-MS Calc. for C₉H₉BrN₂O₅: 305.38; Obs.: 306.2.

Step 3: Synthesis of 6-bromo-2H-pyrido[3,2-b][1,4]oxazin-3(4H)-one (III)

To a stirred solution of ethyl2-((6-bromo-2-nitropyridin-3-yl)oxy)acetate, IIIb (21 g, 0.0687 mol) inglacial acetic acid (400 ml), Iron powder (11.51 g, 0.2063 mol) wasadded and heated to 100° C. for 6 hours. After completion of thereaction, reaction mixture was filtered through celite bed using ethylacetate, 10% Methanol and concentrated in vacuo. It was washed withmethanol to obtain pure 6-bromo-2H-pyrido[3,2-b][1,4]oxazin-3(4H)-one,III (12 g, 76.28%). LC-MS Calc. for C₇HBrN₂O₂: 229.03; Obs.: 230.2.

Synthesis of6-(5-(aminomethyl)-2-oxooxazolidin-3-yl)-2H-pyrido[3,2-b][1,4]oxazin-3(4H)-one(Intermediate IV)

Step 1: (R)-5-(((tert-butyldimethylsilyl)oxy)methyl)oxazolidin-2-one(IVa)

To a stirred solution of TBDMS-Cl (38.46 g, 0.256 mol), imidazole (23.2g, 0.341 mol), DMAP (2.08 g, 0.017 mol) in DMF (200 mL), cooled to 0°C., (R)-5-(hydroxymethyl)oxazolidin-2-one (CAS: 97859-49-9, 20 g, 0.1709mmol) in DMF (25 mL) was added and stirred at 25° C. for 2 h. Aftercompletion of the reaction, reaction mixture was quenched with water andextracted with ethyl acetate. The separated organic layer was washedwith water, brine solution, dried over Na₂SO₄, filtered and concentratedunder reduced pressure. It was purified by column chromatography onsilica gel (230-400 mesh, 20-25% ethyl acetate in pet ether) to obtainIVa (32 g, 81%). LC-MS Calc. for C₁₀H₂₁NO₃Si: 231.37; Obs.: 232.1; ¹HNMR (400 MHz, CDCl₃): δ5.11 (s, 1H), 4.72-4.66 (m, 1H), 3.86-3.82 (m,1H), 3.79-3.76 (m, 1H), 3.66-3.62 (m, 1H), 3.58-3.55 (m, 1H), 0.91 (s,9H), 0.11 (s, 6H).

Step 2:(R)-6-(5-(((tert-butyldimethylsilyl)oxy)methyl)-2-oxooxazolidin-3-yl)-2H-pyrido[3,2-b][1,4]oxazin-3(4H)-one(IVb)

To a stirred solution of IVa (32 g, 0.139 mol) and III (31.7 g, 0.139mol) in dry 1,4-dioxane (50 mL), were added t-butyl-X-Phos mesylchloride complex (5.5 g, 0.0069 mol) and sodium tert-butoxide (19.94 g,0.207 mol) and degassed for 20 mins. Then, it was heated in sealed tubeat 100° C. for 16 h. After completion of the reaction, reaction mixturewas concentrated under reduced pressure. It was purified by columnchromatography on silica gel (230-400 mesh, 25-30% ethyl acetate in petether) to afford IVb (45.6 g, 86%). LC-MS Calc. for C₁₇H₂₅N3O₅Si:379.49; Obs.: 380.0; ¹H NMR (400 MHz, DMSO-d₆): δ 7.60 (d, J=8.68 Hz,1H), 7.43 (d, J=8.68 Hz, 1H), 4.77-4.73 (m, 1H), 4.67 (s, 2H), 4.15-4.10(m, 1H), 3.93-3.89 (m, 3H), 0.79 (s, 9H), 0.04 (s, 6H).

Step 3:(R)-6-(5-(Hydroxymethyl)-2-oxooxazolidin-3-yl)-2H-pyrido[3,2-b][1,4]oxazin-3(4H)-one(IVc)

To a stirred solution of IVb (45 g, 0.118 mol) in TH (250 mL), cooled to0° C., tert-butyl ammonium fluoride (1 M in THF) (296 mL, 0.296 mol) wasadded drop wise and stirred at 25° C. for 3 hours. After completion ofthe reaction, reaction mixture was quenched with water obtained solidfiltered and dried in vacuum to obtain white solid of IVc (29 g, 92%).LC-MS Calc. for C₁₁H₁₁N₃O: 265.23; Obs.: 265.9; H NMR (400 MHz,DMSO-d₆): δ 11.22 (s, 1H), 7.60 (d, J=8.80 Hz, 1H), 7.42 (d, J=8.40 Hz,1H), 5.21 (bs, 1H), 4.70-4.66 (m, 1H), 4.60 (s, 2H), 4.12-4.07 (m, 1H),3.92-3.88 (m, 1H), 3.69-3.65 (m, 1H), 3.54-3.34 (m, 1H).

Step 4:(R)-(2-oxo-3-(3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-6-yl)oxazolidin-5-yl)methylmethanesulfonate (IVd)

To a stirred solution of IVc (29 g, 0.109 mol) in dry DMF (300 mL),cooled to 0° C., triethylamine (45.7 mL, 0.328 mol) and mesyl chloride(17 mL, 0.218 mol) were added and stirred at 25° C. for 2 h. Aftercompletion of the reaction, reaction mixture was quenched with waterobtained solid filtered dried in vacuum to obtain white solid of IVd (30g, 80%). LC-MS Calc. for C₁₂H₁₃N₃O₇S: 343.31; Obs.: 344.0; ¹H NMR (400MHz, DMSO-d6): δ 11.27 (s, 1H), 7.61 (d, J=8.40 Hz, 1H), 7.46 (d, J=8.80Hz, 1H), 5.00 (bs, 1H), 4.63 (s, 2H), 4.63-4.51 (m, 2H), 4.25-4.20 (m,1H), 3.90-3.85 (m, 1H), 3.35 (s, 3H).

Step 5:(R)-6-(5-(azidomethyl)-2-oxooxazolidin-3-yl)-2H-pyrido[3,2-b][1,4]oxazin-3(4H)-one(IVe)

To a stirred solution of IVd (30 g, 0.087 mol) in DMF (300 mL), cooledto 0° C., sodium azide (17 g, 0.262 mol) was added and heated at 60° C.for 3 h. After completion of the reaction, reaction mixture was quenchedwith water obtained solid filtered and dried in vacuo to obtain whitesolid of IVe (22 g, 87%). LC-MS Calc. for C₁₁H₁₀N₆O₄: 290.24; Obs.:290.9; ¹H NMR (400 MHz, DMSO-d₆): δ 11.26 (s, 1H), 7.61 (d, J=8.40 Hz,1H), 7.45 (d, J=8.80 Hz, 1H), 4.88 (bs, 1H), 4.63 (s, 2H), 4.16 (t,J=9.60 Hz, 1H), 3.70-3.84 (m, 3H).

Step 6:(S)-6-(5-(aminomethyl)-2-oxooxazolidin-3-yl)-2H-pyrido[3,2-b][1,4]oxazin-3(4H)-one(IV)

To a stirred solution of IVe (22 g, 0.075 mol) in THF:MeOH (1:1) (400ml), 10% palladium on carbon (7 g) was added and stirred at 25° C. underH₂ for 4 h. After completion of the reaction, reaction mixture wasfiltered through celite bed using THE and MeOH and concentrated underreduced pressure to obtain IV (15 g, 75%). LC-MS Calc. for C₁₁H₁₂N₄O₄:264.24; Obs.: 265.1.

Purification of Intermediate IV:

Boc Protection: To a stirred solution of crude IV (15 g, 0.056 mol) in1, 4 dioxane:water (1:1, 200 mL) was added Na₂CO₃ (12 g, 0.113 mol)followed by the addition of (Boc)₂O (25 g, 0.113 mol) at 0° C. andallowed to stir at rt for 12 h. The reaction mixture was diluted withEtOAc (250 mL) and washed with water (2×250 mL). The combined organiclayers were washed with brine (50 mL), dried over sodium sulphate andevaporated under reduced pressure to get the crude. Crude was purifiedby column chromatography (230/400 mesh, 4% DCM in MeOH) to get desireBoc protected IV as white solid (12 g, 58%). LC-MS Calc. for C₁₆H₂₀N₄O₆:364.36; Obs.: 265.1; ¹H NMR (400 MHz, DMSO-D6): δ 11.23 (s, 1H), 7.61(d, 1H, J=8.8 Hz), 7.45 (d, 1H, J=8.8 Hz), 7.24 (m, 1H), 4.71 (m, 1H),4.60 (s, 2H), 4.16-4.11 (m, 1H), 3.84-3.80 (m, 1H), 3.25 (m, 2H), 1.36(s, 9H).

The Boc protected IV (12 g, 0.033 mmol) was taken in 1, 4 dioxane (60mL) and was added 4M HCl in dioxane (120 mL) at 0° C. to it. Theresulting mixture was stirred at rt for 3 h. The reaction mixture wasconcentrated to obtain crude amine HCl salt. The crude was dissolved indry MeOH/DCM (200 mL) and neutralized with resin, filtered andconcentrated to afford pure amine IV as off white solid (8 g, 92%).LC-MS Calc. for C₁₁H₁₂N₄O₄: 264.24; Obs.: 265.1 [M+H]; ¹H NMR (400 MHz,DMSO-D6): δ 11.05 (brs, 1H), 7.62 (d, 1H, J=8.8 Hz), 7.45 (d, 1H, J=8.8Hz), 7.05 (brs, 2H), 4.83 (m, 1H), 4.62 (s, 2H), 4.23-4.20 (m, 1H),3.87-3.82 (m, 1H), 3.19-3.10 (m, 2H).

Synthesis of 6-chloro-2H-pyrazino[2,3-b][1,4]oxazin-3(4H)-one(Intermediate Va)

To a stirred solution of 3-bromo-6-chloropyrazin-2-amine (75 g, 0.3598mol) in 1,4-dioxane (1500 mL) at room temperature under nitrogenatmosphere was added sodium tert-butoxide (110.65 g, 1.1514 mol) andstirred for 30 minutes. Then ethyl glycolate (112.37 g, 1.0794 mol) wasadded dropwise over a period of 30 minutes at room temperature. Theresulting mixture was heated to 100° C. and stirred for 2 hours. Theprogress of the reaction was monitored by TLC.

After that the reaction mixture was cooled to room temperature andconcentrated under reduced pressure to remove the dioxane. The residueobtained was diluted with water (750 mL) and neutralized using HCl (1.5N). The precipitated solid was filtered out and dried under vacuum toget the compound Va as an off white solid. Yield: 60 g, 89.9%; LC-MSCalc. for C₆H₄CN₃O₂, 185.57, Observed 184.0 (M−1H); ¹H NMR (400 MHz,DMSO-d6): δ 11.86 (s, 1H), 7.87 (s, 1H), 4.90 (s, 2H).

Synthesis of(S)-6-(5-(aminomethyl)-2-oxooxazolidin-3-yl)-2H-pyrazino[2,3-b][1,4]oxazin-3(4H)-one,(Intermediate V)

Step 1:(R)-6-(5-(((tert-butyldimethylsilyl)oxy)methyl)-2-oxooxazolidin-3-yl)-2H-pyrazino[2,3-b][1,4]oxazin-3(4H)-one(Vb)

To a stirred solution of Va (2.5 g, 13.51 mmol) and IIIa (3.43 g, 14.86mmol) in dry 1,4-Dioxane (40 mL), were added t-butyl-X-Phos mesylchloride complex (0.53 g, 0.67 mmol) and sodium tert-butoxide (1.94 g,20.27 mmol) and degassed for 20 mins. Then, it was heated in sealed tubeat 100° C. for 16 h. After completion of the reaction, reaction mixturewas concentrated under reduced pressure. It was purified by columnchromatography on silica gel (230-400 mesh, 25-30% ethyl acetate in petether) to afford Vb (3 g, 59%). LC-MS Calc. for C₁₆H₂₄N₄O₅Si, 380.48,Observed 381.1 (M⁺1H); ¹H NMR (400 MHz, DMSO-d₆): δ 11.61 (s, 1H),8.37-8.35 (m, 1H), 4.85-4.79 (m, 3H), 4.12-4.06 (m, 1H), 3.89-3.74 (m,3H), 0.84-0.71 (m, 9H), 0.03-0.00 (m, 6H).

Step 2:(R)-6-(5-(hydroxymethyl)-2-oxooxazolidin-3-yl)-2H-pyrazino[2,3-b][1,4]oxazin-3(4H)-one(Vc)

To a stirred solution of Vb (3 g, 7.89 mmol) in THE (30 mL), cooled to0° C., tert-butyl ammonium fluoride (1 M in THF) (15.8 mL, 15.78 mmol)was added dropwise and stirred at room temperature for 3 hours. Aftercompletion of the reaction, reaction mixture was quenched with water,extracted with ethyl acetate, dried over sodium sulphate and evaporated.The crude was purified by column chromatography on silica gel (230-400mesh, 50-50% ethyl acetate in pet ether) to afford Vc (1.5 g, 71%).LC-MS Calc. for C₁₀H₁₀N₄O, 266.21, Observed 267.1 (M⁺1H); ¹H NMR (400MHz, DMSO-d₆): δ 11.62 (s, 1H), 8.38 (s, 1H), 5.23-5.07 (m, 2H), 5.03(s, 1H), 4.86-4.73 (m, 1H), 4.10-3.86 (m, 2H), 3.70-3.48 (m, 2H).

Alternative Route for the Synthesis of Vc

To a stirred solution of Va (40.0 g, 0.215 mol) and(R)-5-(hydroxymethyl)oxazolidin-2-one (CAS: 97859-49-9, 28.0 g, 0.237mol) in 1.4-dioxane (600 mL) was added sodium tert-butoxide (31.08 g,0.323 mol) at room temperature. The resulting mixture was degassed witha stream of nitrogen and was added t-butyl-X-Phos Palladacycle (8.56 g,0.0107 mol) at room temperature. The resulting mixture was then heatedto 100° C. and stirred for 3 hours. After that, the reaction mixture wascooled to room temperature, concentrated in vacuo. The residue obtainedwas diluted with water (500 mL), neutralised with 1.5 N HCl (pH˜7). Thesolid precipitated out was filtered and washed with diethyl ether, driedunder vacuo to get compound Vc as brown solid. Yield: 55.0 g (crude),95.9%.

Step 3:(R)-(2-oxo-3-(3-oxo-3,4-dihydro-2H-pyrazino[2,3-b][1,4]oxazin-6-yl)oxazolidin-5-yl)methylmethanesulfonate (Vd)

To a stirred solution of Vc (1.5 g, 5.63 mmol) in dry DMF (15 mL),cooled to 0° C., Triethylamine (2.3 mL, 16.91 mmol) and mesyl chloride(0.69 mL, 8.45 mmol) were added and stirred at 25° C. for 2 h. Aftercompletion of the reaction, reaction mixture was quenched with water,the resultant solid was filtered, washed with pet ether and dried byvacuum to afford brown solid of Vd (1.2 g, 63%). LC-MS Calc. forC₁₁H₁₂N₄O₇S, 344.30, Observed 345.0 (M⁺1H); ¹H NMR (400 MHz, DMSO-d₆): δ11.67 (s, 1H), 8.38 (s, 1H), 5.06-5.04 (m, 1H), 4.87 (s, 2H), 4.57-4.54(m, 2H), 4.23-4.20 (m, 1H), 3.86-3.82 (m, 1H), 3.28 (s, 3H), 3.25-3.23(m, 1H).

Step 4: (R)-6-(5-(azidomethyl)-2-oxooxazolidin-3-yl)-2H-pyrazino[2,3-b][1,4]oxazin-3(4H)-one (Ve)

To a stirred solution of Vd (1.2 g, 3.48 mmol) in DMF (12 mL), cooled to0° C., sodium azide (0.56 g, 8.72 mmol) was added and heated at 65° C.for 3 h. After completion of the reaction, reaction mixture was quenchedwith water, the obtained solid was filtered, washed with pet ether anddried to afford the brown solid Ve (0.7 g, 70%). LC-MS Calc. forC₁₀H₉N₇O₄, 291.23, Observed 290.1 (M−1H); ¹H NMR (400 MHz, DMSO-d₆): δ11.66 (s, 1H), 4.94-4.86 (m, 3H), 4.18-4.13 (m, 1H), 3.81-3.75 (m, 3H).

Step 5(S)-6-(5-(aminomethyl)-2-oxooxazolidin-3-yl)-2H-pyrazino[2,3-b][1,4]oxazin-3(4H)-one(V)

To a stirred solution of Ve (0.7 g, 2.40 mmol) in THF:MeOH (1:1) (40 ml)was added PPh₃ (1.9 g, 7.21 mmol) at room temperature. The reactionmixture was heated at 70° C. for 3 h. After completion of the reactionby TLC, reaction mixture was cooled to room temperature, and wasextracted with ethyl acetate (2×100 ml) for 2 times. Further the aqueouslayer was concentrated and dried to afford V (0.3 g, 47%). LC-MS Calc.for C₁₀H₁₁NO₄, 265.23, Observed 264.1 (M−1H); ¹H NMR (400 MHz, DMSO-d₆):δ 8.38 (s, 1H), 4.85 (s, 2H), 4.69-4.67 (m, 1H), 4.11-4.06 (m, 1H),3.88-3.84 (m, 1H), 3.17 (s, 1H), 2.91-2.83 (m, 2H).

Synthesis of(R)-6-(5-(aminomethyl)-2-oxooxazolidin-3-yl)-2H-pyrazino[2,3-b][1,4]oxazin-3(4H)-one(Intermediate VI)

Intermediate VI was synthesized using scheme and procedures analogues toIntermediate V involving (S)-5-(hydroxymethyl)oxazolidin-2-one (CAS:97859-49-9) and 6-chloro-2H-pyrazino[2,3-b][1,4]oxazin-3(4H)-one (Va) asstarting materials. LC-MS Calc. for C₁₀H₁₁N₅O₄, 265.23, Observed 264.2(M−1H); ¹H NMR (400 MHz, DMSO-d₆): δ 8.36 (s, 1H), 4.84 (s, 2H),4.69-4.65 (m, 1H), 4.12-4.06 (m, 1H), 3.89-3.84 (m, 1H), 3.16 (s, 1H),2.92-2.83 (m, 2H).

Synthesis of 6-chloro-2H-pyrazino[2,3-b][1,4]thiazin-3(4H)-one, VIIa

To a stirred solution of 3-bromo-6-chloropyrazin-2-amine I (10 g, 0.0479mol) in 1, 4-dioxane (1.5 L) at room temperature under nitrogenatmosphere was added sodium tert-butoxide (14.75 g, 0.1535 mol) andstirred for 30 minutes. Then ethyl thioglycolate (11.53 g, 0.0959 mol)was added in dropwise over a period of 30 minutes at room temperature.The resulting mixture was heated to 100° C. and stirred for 2 hours. Theprogress of the reaction was monitored by TLC.

After that, the reaction mixture was cooled to room temperature andconcentrated under reduced pressure to remove the dioxane. The residueobtained was diluted with water (750 mL) and neutralized using HCl (1.5N). The precipitated solid was filtered out and dried to get thecompound VIIa as an off white solid. Yield: 6 g, 62.5%; LC_MS: Calc. forC₆H₄CN₃O_(S): 201.63; Obs.: 199.9 [M−1H]. ¹H-NMR (400 MHz, DMSO-d₆): δ11.54 (s, 1H), 8.25 (s, 1H), 3.83 (s, 2H).

Synthesis of(S)-5-(aminomethyl)-3-(3-oxo-3,4-dihydro-2H-pyrazino[2,3-b][1,4]thiazin-6-yl)oxazolidin-2-one(Intermediate VII)

Step 1:(R)-5-(hydroxymethyl)-3-(3-oxo-3,4-dihydro-2H-pyrazino[2,3-b][1,4]thiazin-6-yl)oxazolidin-2-one(VIIb)

To a stirred solution of compound VIIa (6 g, 0.0297 mol) and(R)-5-(hydroxymethyl)oxazolidin-2-one (CAS: 97859-49-9, 3.83 g, 0.0327mol) in 1.4-dioxane (100 mL) was added sodium tert-butoxide (4.29 g,0.0446 mol) at room temperature. The resulting mixture was degassed witha stream of nitrogen for 10 minutes. Then t-butyl-X-Phos Palladacycle(1.18 g, 0.0014 mol) was added at room temperature and again degassedwith nitrogen for 5 minutes. The resulting mixture was then heated to100° C. and stirred for 5 hours. After that, the reaction mixture wascooled to room temperature and concentrated in vacuo. The residueobtained was diluted with water (50 mL), neutralized with aqueous HCl(1.5 N, pH˜7). The solid precipitated out was filtered and washed withdiethyl ether, dried under vacuo to get compound VIIb as brown solid.Yield: 4 g (crude), which was taken for the next step without anyfurther purification. LC_MS: Calc. for C₁₀H₁₀N₄O₄S: 282.27; Obs.: 283.2[M+H]+. ¹H NMR (300 MHz, DMSO-d₆): δ 11.24 (s, 1H), 8.24 (s, 1H),5.27-5.24 (m, 1H), 4.80-4.76 (m, 1H), 4.09 (t, J=9.36 Hz, 1H), 3.91-3.87(m, 1H), 3.78-3.68 (m, 3H), 3.60-3.57 (m, 1H).

Step 2:(R)-(2-oxo-3-(3-oxo-3,4-dihydro-2H-pyrazino[2,3-b][1,4]thiazin-6-yl)oxazolidin-5-yl)methylmethanesulfonate (VIIb)

To a stirred solution of VIIa (4 g, 0.0141 mol) in dry DMF (40 mL) at 0°C. under nitrogen atmosphere were added triethylamine (5.5 mL, 0.0425mol) and mesyl chloride (2.43, 0.0215 mol) successively. The reactionmixture was then warmed to room temperature and stirred for 2 h. Afterthat the reaction mixture was quenched with water, the solid formed wasfiltered, washed with petroleum ether and dried to get compound VIIb asa brown solid (3 g, crude), which was taken for the next step withoutany further purification. LC_MS: Calc. for C₁₁H₂N₄O₆S₂: 360.36; Obs.:361.00 [M+H]⁺.

Step 3:(R)-5-(azidomethyl)-3-(3-oxo-3,4-dihydro-2H-pyrazino[2,3-b][1,4]thiazin-6-yl)oxazolidin-2-one(VIIc)

To a stirred solution of VIIb (3.0 g, 0.0083 mol) in DMF (30 mL) at 0°C. under nitrogen atmosphere was added sodium azide (2.16 g, 0.033 mol).The reaction mixture was then heated to 65° C. and stirred for 3 h.After that, reaction mixture was quenched with water, the solid obtainedwas filtered, washed with petroleum ether and dried to get compound VIIcas a brown solid (1.7 g, 66.66%). LC_MS: Calc. for C₁₀H₉N₇O₃S: 307.29;Obs.: 307.9 [M+H]⁺.

Step 4:(S)-5-(aminomethyl)-3-(3-oxo-3,4-dihydro-2H-pyrazino[2,3-b][1,4]thiazin-6-yl)oxazolidin-2-one(VII)

To a stirred solution of compound VIIc (1.7 g, 0.0055 mol) in a mixtureof THF:H₂O (1:1) (80 mL) under nitrogen atmosphere was added PPh₃ (4.34g, 0.0165 mol) at room temperature. The reaction mixture was heated to70° C. and stirred for 3 hours. After completion of the reaction by TLC,the reaction mixture was cooled to room temperature and extracted withethyl acetate (2×100 mL). The aqueous layer was separated andconcentrated in vacuo to get compound VII (0.9 g, 58.06%). LC_MS: Calc.for C₁₀H₁₁N₅O₃S: 281.29; Obs.: 282.1 [M+H]⁺.

Synthesis of2-(6-Fluoro-4-methyl-3-oxo-3,4-dihydroquinoxalin-5-yl)acetaldehyde,(Intermediate VIII)

Step 1: 2-Bromo-1, 3-difluoro-4-nitrobenzene (VIIIa)

To a stirred solution of 2-bromo-1,3-difluorobenzene (CAS 64248-56-2,10.0 g, 51.8 mmol) in H₂SO₄ (30 mL) at 0° C. under nitrogen atmospherewas added HNO₃ (65%, 25 mL) in dropwise. The resulting mixture waswarmed to room temperature and stirred for 1 hour. After that, thereaction mixture was poured onto ice and vigorously stirred for 5minutes. The resulting suspension was extracted with CH₂Cl₂ (4×125 mL),washed with brine (200 mL), dried over Na₂SO₄ and concentrated in vacuoto get compound VIIIa (crude). The obtained crude product was taken forthe next step without any further purification. Yield: 9.00 g, 72.99%.¹H-NMR (400 MHz, DMSO-d₆): δ 8.34-8.29 (m, 1H), 7.56-7.51 (m, 1H).

Step 2: 2-Bromo-3-fluoro-N-methyl-6-nitroaniline (VIIIb)

To a stirred solution of compound VIIIa (9.00 g, 37.8 mmol) and DIPEA(13.3 mL, 75.6 mmol) in THE (90 mL) at room temperature under nitrogenatmosphere was added methylamine (2M in THF, 37.8 mL, 75.6 mmol). Theresulting mixture was heated to 60° C. and stirred for 3 hours. Afterthat, the reaction mixture was concentrated under reduced pressure andthe residue obtained was purified by column chromatography using silicagel (60-120 mesh) eluting with petroleum ether to give compound VIIb aspale yellow colour solid. Yield: 7.70 g, 81.74%. ¹H-NMR (400 MHz,DMSO-d₆): δ 7.91-7.87 (m, 1H), 6.80-6.76 (m, 2H), 2.75 (s, 3H).

Step 3: 6-Bromo-5-fluoro-N₁-methylbenzene-1, 2-diamine (VIIIc)

To a stirred solution of compound VIIb (7.70 g, 30.9 mmol) in a mixtureof methanol/water (400 mL, 3:1) were added ammonium chloride (8.20 g,154.6 mmol) and iron powder (6.90 g, 123.7 mmol) successively. Theresulting mixture was heated at reflux for 16 hours. After that, thereaction mixture was filtered to the solid material and the filtrate wasconcentrated under reduced pressure. The residue obtained was dilutedwith water and extracted with ethyl acetate (2×300 mL). The combinedorganic phase was washed with brine, dried over Na₂SO₄ and concentratedin vacuo. The obtained residue was further purified by columnchromatography using silica gel (230-400 mesh) eluting with 15-20% ethylacetate in petroleum ether to get compound VIIIc as pale brown coloursolid. Yield: 3.50 g, 51.69%; ¹H NMR (400 MHz, DMSO-d₆): δ 6.70 (t,J=8.6 Hz, 1H), 6.61-6.59 (m, 1H), 4.82 (brs, 2H), 3.92 (brs, 1H), 2.61(s, 3H).

Step 4: Ethyl (3-bromo-4-fluoro-2-(methylamino) phenyl) glycinate(VIIId)

To a stirred solution of compound VIIIc (3.50 g, 16.0 mmol) in DMF (70mL) at 0° C. under nitrogen atmosphere were added K₂CO₃ (3.30 g, 23.9mmol) and ethyl bromoacetate (2.10 mL, 19.2 mmol) successively. Theresulting mixture was heated to 75° C. and stirred for 1 hour. Uponcompletion, the reaction mixture was quenched with ice cold water (50mL) and extracted with ethyl acetate (4×100 mL). The combined organicphase was washed with brine, dried over Na₂SO₄ and concentrated invacuo. The obtained crude product was purified by column chromatographyusing silica gel (230-400 mesh) eluting with 10-15% of ethyl acetate inpetroleum ether to get compound VIIId. Yield: 3.50 g, 71.86%. ¹H-NMR(400 MHz, DMSO-d₆): δ 6.84 (t, J=8.6 Hz, 1H), 6.41-6.38 (m, 1H),5.39-5.37 (m, 1H), 4.16-4.08 (m, 1H), 4.01-3.94 (m, 1H), 2.59 (d, J=5.7Hz, 3H), 1.18 (t, J=7.0 Hz, 3H).

Step 5: 8-Bromo-7-fluoro-1-methyl-3,4-dihydroquinoxalin-2(1H)-one(VIIIe)

To a stirred solution of compound VIIId (3.50 g, 11.5 mmol) in 1,4-Dioaxne (70 mL) at 0° C. under nitrogen atmosphere was added NaH (60%dispersion in oil, 0.14 g, 3.44 mmol). The resulting mixture was heated100° C. and stirred for 2 hours. After that, reaction mixture wasquenched with ice cold water (50 mL) and extracted with ethyl acetate(3×100 mL). The combined organic phase was washed with brine (100 mL),dried over Na₂SO₄ and concentrated in vacuo. The obtained crude productwas further purified by column chromatography using silica gel (230-400mesh) eluting with 25-30% of ethyl acetate in petroleum ether to getcompound VIIIe as off-white solid. Yield: 2.70 g, 90.91%. ¹H-NMR (400MHz, DMSO-d₆): δ 6.99-6.94 (m, 1H), 6.88-6.84 (m, 1H), 6.24 (s, 1H),3.60 (s, 2H), 3.35 (s, 3H).

Step 6: 8-Bromo-7-fluoro-1-methylquinoxalin-2(1H)-one (VIIIf)

To a stirred solution of compound VIIIe (2.7 g, 10.42 mmol) in 1,4-dioxane (30 mL) at room temperature under nitrogen atmosphere wasadded MnO₂ (5.44 g, 62.54 mmol) at once. The resulting mixture washeated to 100° C. and stirred for 2 hours. After that the reactionmixture was cooled to room temperature, filtered through celite pad andthoroughly washed with ethyl acetate. The combined filtrate wasconcentrated under reduced pressure to get compound VIIIf (crude) as apale brown solid, which was used for the next step without any furtherpurification. Yield: 2.1 g (crude). ¹H-NMR (300 MHz, DMSO-d₆): δ 8.24(s, 1H), 7.91-7.86 (m, 1H), 7.46-7.40 (m, 1H), 3.91 (s, 3H).

Step 7: 7-Fluoro-8-hydroxy-1-methylquinoxalin-2(1H)-one (VIIIg)

A stirred solution of compound VIIIf (2.1 g, 8.17 mmol) in a mixture of1,4-dioxane (25 mL) and water (15 mL) at room temperature was degassedwith a stream of nitrogen for 15 minutes. Then t-BuXPhos Palladacycle(0.19 g, 0.24 mmol) and tris (dibenzylideneacetone)dipalladium (0) (0.15g, 0.16 mmol) were added successively. The resulting mixture was againdegassed with stream of nitrogen for 10 minutes. Then KOH (0.91 g, 16.34mmol) was added to the reaction mixture under nitrogen atmosphere. Theresulting mixture was then heated to 100° C. and stirred for 16 hours.

After that the reaction mixture was cooled to 0° C., quenched with waterand washed with ethyl acetate (2×50 mL). The aqueous phase was thenacidified with 1.5 HCl (5 mL) and extracted with ethyl acetate (3×50mL). The combined organic phase was washed with brine solution (50 mL),dried over Na₂SO₄ and concentrated in vacuo to get compound VIIIg(crude) as a pale brown solid. The crude product was taken for the nextstep without any further purification. Yield: 1.1 g, 69.62%. LC_MS:Calc. for C₉H₇FN₂O₂ 194.17; Obs.: 194.9 [M+H]⁺.

Step 8: 8-(2,2-Diethoxyethoxy)-7-fluoro-1-methylquinoxalin-2(1H)-one(VIIIh)

To a stirred solution of compound VIIIg (1.1 g, 5.67 mmol) in dimethylsulfoxide (11 mL) at room temperature under nitrogen atmosphere wereadded cesium carbonate (2.57 g, 7.93 mmol) and bromoacetaldehyde diethylacetal (1.4 mL, 8.50 mmol) successively. The resulting mixture washeated to 90° C. and stirred for 16 hours. After that the reactionmixture was diluted with water (20 mL) and extracted with ethyl acetate(3×25 mL). The combined organic phase was washed with brine solution,dried over Na₂SO₄ and concentrated in vacuo. The obtained crude productwas further purified by column chromatography using silica gel (230-400mesh) eluting with 15% ethyl acetate in petroleum ether to get compoundVIIIh as a pale brown solid. Yield: 1.2 g, 70.58%. LC_MS: Calc. forC₁₅H₁₉FN₂O₄ 310.33; Obs.: 311.2 [M+H]⁺.

Step 9:2-((6-Fluoro-4-methyl-3-oxo-3,4-dihydroquinoxalin-5-yl)oxy)acetaldehyde(VIII)

To a stirred solution of compound VIIIh (1.2 g, 3.86 mmol) indichloromethane (15 mL) at 0° C. under nitrogen atmosphere was addedtrifluoroacetic acid (6 mL, 5 volume) in dropwise. The resulting mixturewas allowed to stir at room temperature for 2 hours. After that thereaction mixture was concentrated, basified with 10% NaHCO₃ solution,extracted with dichloromethane (3×50 mL), dried over Na₂SO₄ andconcentrated in vacuo to get compound VIII (crude) as a brown solid. Thecrude product was used as such for the next step without furtherpurification. Yield: 0.6 g. LC_MS: Calc. for C₁₁H₉FN₂O₃ 236.2; Obs.237.0 [M+H]⁺.

Synthesis of 2-(7-fluoro-1,4-dimethyl-2-oxo-1,2-dihydroquinolin-8-yl)acetaldehyde, (IntermediateIX)

Step 1: N-(2-Bromo-3-fluorophenyl) acetamide (IXa)

To a stirred solution of 2-bromo-3-fluoro aniline (25.0 g, 131.57 mmol)in dichloromethane (500 mL) at 0° C. under nitrogen was added aceticanhydride (18.65 mL, 197.36 mmol). The resulting mixture was warmed toroom temperature and stirred for 16 hours. After that, the reactionmixture was diluted water and extracted with dichloromethane (2×500 mL).The combined organic phase was washed with brine, dried over anhydrousNa₂SO₄ and concentrated in vacuo to get compound IXa (crude), which wastaken as such for the next step without further purification. Yield: 25g, 81.91%. LC-MS Calc. for C₈H₇BrFNO, 232.05; Obs.; 232.0 [M⁺]; ¹H-NMR(300 MHz, DMSO-d₆): δ 9.57 (s, 1H), 7.49-7.34 (m, 2H), 7.20-7.14 (m,1H), 2.09 (s, 3H).

Step 2: N-(2-Bromo-3-fluorophenyl)-N-methylacetamide (IXb)

To a stirred solution of compound IXa (25.0 g, 107.73 mmol) in dry THF(500 mL) under nitrogen atmosphere was added sodium hydride (60% inmineral oil, 5.38 g, and 134.66 mmol) and stirred for 30 minutes. Thendimethyl sulphate (13.79 mL, 145.44 mmol) was added to the reactionmixture at 0° C. The resulting mixture was warmed to room temperatureand stirred at room temperature for 3 hours. After that, the reactionmixture was diluted with water and extracted with ethyl acetate (2×500mL). The combined organic phase was washed with brine, dried over sodiumsulfate and concentrated in vacuo to get compound IXb as a white solid,which was used as such for the next step without further purification.Yield: 20 g, 75.47%. LC-MS Calc. for C₉H₉BrFNO 246.08; Obs.: 248.0;[M⁺+2H]; ¹H NMR (300 MHz, DMSO-d₆): δ 7.58-7.32 (m, 3H), 3.05 (s, 3H),1.67 (s, 3H).

Step 3: Ethyl4-((2-bromo-3-fluorophenyl)(methyl)amino)-2,4-dioxobutanoate (IXc)

To a stirred solution of compound IXb (20.0 g, 81.95 mmol) in sodiumethoxide (20% in ethanol, 55 mL, 163.90 mmol) at room temperature undernitrogen atmosphere was added diethyl oxalate (47.89 g, 327.81 mmol).The resulting mixture was then heated at 80° C. and stirred for 16hours. After that, the reaction mixture was completely evaporated underreduced pressure to get crude compound, which was further purified bycolumn chromatography silica gel (230-400 mesh, 40% EtOAc in Petroleumether) to get compound IXc as a colorless oil. Yield: 15.0 g, 53.32%.LC-MS Calc. for C₁₃H₃BrFNO₄ 346.15; Obs.: 347.0 [M⁺+H]; ¹H NMR (400 MHz,DMSO-d₆): δ 7.63-7.48 (m, 3H), 5.37 (s, 1H), 4.18-4.13 (m, 2H), 3.22 (s,3H), 1.30-1.15 (m, 3H).

Step 4: 8-Bromo-7-fluoro-1-methyl-2-oxo-1,2-dihydroquinoline-4-carboxylic acid (IXd)

A solution of compound IXc (23.0 g, 66.44 mmol) in Con H₂SO₄ (230 mL)was heated to 90° C. and stirred for 16 hours. After that, the reactionmixture was quenched with ice cold water and extracted with ethylacetate (2×500 mL), washed with water, brine, dried over sodium sulfateand concentrated in vacuo. The obtained crude product was furthertriturated with diethyl ether, filtered and dried to get compound IXd asa white solid, which was used as such for the next step without furtherpurification. Yield: 15 g, 75.26%. LC-MS Calc. for C₁₁H₇BrFNO₃ 300.08;Obs.: 300.0; [M⁺]; ¹H NMR (400 MHz, DMSO-d₆): δ 14.22 (s, br, 1H),8.25-8.22 (m, 1H), 7.40-7.35 (m, 1H), 6.95 (s, 1H), 3.81 (s, 3H).

Step 5: 8-Bromo-7-fluoro-4-(hydroxymethyl)-1-methylquinolin-2(1H)-one(IXe)

To a stirred solution of compound IXd (12.0 g, 40.00 mmol) in THE (120mL) at 0° C. under nitrogen atmosphere were added triethylamine (7.23mL, 52.00 mmol) and isobutyl chloroformate (6.55 g, 48 mmol)successively and stirred for 1 hour. Then NaBH₄ (3.80 g, 100.00 mmol) inportions and methanol (10 mL) were added to the reaction mixture andcontinued to stir for 10 minutes. After that, the reaction mixture wasdiluted with water and extracted with ethyl acetate (2×500 mL). Thecombined organic phase was washed with brine, dried over sodium sulfateand concentrated in vacuo. The obtained crude product was purified bycolumn chromatography silica gel (230-400 mesh, 40% EtOAc in petroleumether) to get compound IXe as a white solid. Yield: 6.5 g, 56.82%. LC-MSCalc. for C₁₁H₉BrFNO₂, 286.10; Obs.: 288.0 [M⁺+2H]; ¹H NMR (400 MHz,DMSO-d₆): δ 7.82-7.78 (m, 1H), 7.34-7.30 (m, 1H), 6.68 (s, 1H),5.61-5.58 (m, 1H), 4.74-4.72 (m, 2H), 3.80 (s, 3H).

Step 6: 8-Bromo-4-(chloromethyl)-7-fluoro-1-methylquinolin-2(1H)-one(IXf)

To a stirred solution of compound IXe (3.0 g, 10.48 mmol) indichloromethane (60 mL) at 0° C. under nitrogen atmosphere was addedthionyl chloride (2.34 mL, 31.46 mmol) in dropwise. The resultingmixture was then warmed to room temperature and stirred for 5 hours.After that, the reaction mixture was quenched with 10% aqueous NaHCO₃solution and extracted with dichloromethane (2×100 mL). The combinedorganic extract was washed with brine, dried over sodium sulfate andconcentrated in vacuo. The obtained crude product was further purifiedby column chromatography using silica gel (230-400 mesh) eluting with20% EtOAc in petroleum ether) to get compound IXf as an off-white solid.Yield: 1.5 g, 47.16%. LC-MS Calc. for C₁₁H₈BrClFNO, 304.54; Obs.: 306.0[M⁺+2H]; ¹H-NMR (300 MHz, DMSO-d₆): δ 7.98-7.93 (m, 1H), 7.44-7.39 (m,1H), 6.87 (s, 1H), 5.04 (s, 2H), 3.81 (s, 3H).

Step 7: 8-Bromo-7-fluoro-1, 4-dimethylquinolin-2(1H)-one (IXg)

To a stirred solution of compound IXf (1.5 g, 4.93 mmol) in DMF (30 mL)at 0° C. under nitrogen atmosphere was added NaBH₄ (93 mg, 2.46 mmol).The resulting mixture was warmed to room temperature and stirred for 3hours. After that, the reaction mixture was cooled to 0° C., quenchedwith water (60 mL) and extracted with ethyl acetate (2×100 mL). Thecombined organic phase was washed with brine, dried over sodium sulfateand concentrated in vacuo. The obtained crude product was furtherpurified by column chromatography using silica gel (230-400 mesh) 20%ethyl acetate in petroleum ether) to get compound IXg as an off-whitesolid. Yield: 0.7 g, 53.84%. LC-MS Calc. for C₁₁H₉BrFNO, 270.10; Obs.:272.0 [M⁺+2H]; ¹H NMR (400 MHz, DMSO-d₆): δ 7.83 (m, 1H), 7.31 (m, 1H),6.55 (s, 1H), 3.78 (s, 3H), 2.40 (s, 3H).

Step 8: 7-Fluoro-8-hydroxy-1,4-dimethylquinolin-2(1H)-one (IXh)

A stirred solution of compound IXg (1.0 g, 3.7037 mmol) in a mixture of1,4-dioxane (15 mL) and water (5 mL) at room temperature was degassedwith a stream of nitrogen for 15 minutes. Then t-BuXPhos Palladacycle(90 mg, 0.1111 mmol) and tris (dibenzylideneacetone)dipalladium (0) (68mg, 0.074 mmol) were added successively. The resulting mixture was againdegassed with stream of nitrogen for 10 minutes. Then KOH (0.415 g,7.4074 mmol) was added to the reaction mixture under nitrogen atmosphereat room temperature. The resulting mixture was then heated to 100° C.and stirred for 16 hours.

After that the reaction mixture was cooled to 0° C., quenched with waterand washed with ethyl acetate (2×50 mL). The aqueous phase separated wasthen acidified with HCl (1.5 N, 5 mL) and extracted with ethyl acetate(3×50 mL). The combined organic phase was washed with brine solution (50mL), dried over Na₂SO₄ and concentrated in vacuo to get compound IXh(crude) as a pale brown solid, which was taken for the next step withoutany further purification. Yield: 0.5 g, 65.86%. LC_MS: Calc. forC₁₁H₁₀FNO₂ 207.2; Obs.: 208.1 [M+H]⁺.

Step 9: 8-(2,2-Diethoxyethoxy)-7-fluoro-1,4-dimethylquinolin-2(1H)-one(IXi)

To a stirred solution of compound IXh (0.5 g, 2.41 mmol) in dimethylsulfoxide (10 mL) at room temperature under nitrogen atmosphere wereadded cesium carbonate (1.1 g, 3.38 mmol) and bromoacetaldehyde diethylacetal (0.55 mL, 3.62 mmol. The reaction mixture was then heated to 90°C. and stirred for 16 hours. After that the reaction mixture was dilutedwith water (20 mL) and extracted with ethyl acetate (3×25 mL). Thecombined organic phase was washed with brine solution, dried over Na₂SO₄and concentrated in vacuo. The obtained crude product was furtherpurified by column chromatography using silica gel (230-400 mesh)eluting with 15% ethyl acetate in petroleum ether to get compound IXi asa pale brown solid. Yield: 0.5 g, 64.1%. LC_MS: Calc. for C₁₇H₂₂FNO₄323.36; Obs.: 324.1 [M+H]⁺.

Step 10:2-((7-Fluoro-1,4-dimethyl-2-oxo-1,2-dihydroquinolin-8-yl)oxy)acetaldehyde(IX)

To a stirred solution of compound IXi (0.5 g, 1.54 mmol) indichloromethane (10 mL) at 0° C. under nitrogen atmosphere was addedtrifluoroacetic acid (5 mL, 10 volume) in dropwise. The resultingmixture was allowed to stir at room temperature for 2 hours. After thatthe reaction mixture was concentrated, basified with 10% NaHCO₃solution, extracted with dichloromethane (3×50 mL). The combined organicextract was dried over anhydrous Na₂SO₄ and concentrated in vacuo to getcompound IX (crude) as a brown solid, which was used for the next stepwithout further purification. Yield: 0.25 g. LC_MS: Calc. for C₁₃H₂FNO₃249.24; Obs. 250.1 [M+H]+; ¹H-NMR (300 MHz, DMSO-d₆): δ 9.67 (s, 1H),7.60-7.55 (m, 1H), 7.29-7.22 (m, 1H), 6.53 (s, 1H), 4.88 (s, 2H), 3.79(s, 3H), 2.49 (s, 3H).

Synthesis of 7-Fluoro-1-methyl-8-(2-oxopropoxy)quinolin-2(1H)-one(Intermediate X)

To a stirred solution of compound IIa (0.6 g, 3.10 mmol) in DMF (6 mL)at room temperature under nitrogen atmosphere were added potassiumcarbonate (0.65 g, 4.66 mmol) and chloroacetone (0.46 g, 4.96 mmolsuccessively. The reaction mixture was then warmed to room temperatureand stirred for 16 hours. After that the reaction mixture was dilutedwith water (20 mL) and extracted with ethyl acetate (3×25 mL). Thecombined organic phase was washed with brine solution, dried over Na₂SO₄and concentrated in vacuo. The obtained crude product was furtherpurified by column chromatography using silica gel (230-400 mesh)eluting with 10% ethyl acetate in petroleum ether to get compound X as abrown solid. Yield: 0.26 g, 33.76%. LC_MS: Calc. for C₁₃H₁₂FNO₃ 249.24;Obs.: 250.1 [M+H]⁺.

Synthesis of2-((6-fluoro-2,4-dimethyl-3-oxo-3,4-dihydroquinoxalin-5-yl)oxy)acetaldehyde,(Intermediate XI)

Step 1: 8-Bromo-7-fluoro-1, 3-dimethylquinoxalin-2(1H)-one (XIa)

To a stirred solution of compound VIIIc (3.00 g, 13.7 mmol) in ethanol(15 mL) at room temperature under nitrogen atmosphere were added ethylpyruvate (1.52 mL, 13.7 mmol) and acetic acid (15 mL) successively. Theresulting mixture was heated to reflux and stirred for 16 hours. Afterthat, the reaction mixture was concentrated under reduced pressure. Theresidue obtained was diluted with water (100 mL) and extracted withethyl acetate (2×50 mL). The combined organic phase was washed withbrine (50 mL), dried over Na₂SO₄ and evaporated in vacuo. The obtainedcrude product was further purified by column chromatography using silicagel (230-400 mesh) eluting with 20-30% ethyl acetate in petroleum etherto get compound XIa as an off-white solid. Yield: 2.30 g, 61.99%; ¹H-NMR(400 MHz, DMSO-d₆): δ 7.82-7.78 (m, 1H), 7.41-7.37 (m, 1H), 3.91 (s,3H), 2.42 (s, 3H).

Step 2: 7-Fluoro-8-hydroxy-1,3-dimethylquinoxalin-2(1H)-one (XIb)

A stirred solution of compound XIa (2.1 g, 7.74 mmol) in a mixture of1,4-dioxane (25 mL) and water (15 mL) at room temperature was degassedwith a stream of nitrogen for 15 minutes. Then t-BuXPhos Palladacycle(0.18454 g, 0.234 mmol) and tris (dibenzylideneacetone)dipalladium (0)(0.141 g, 0.16 mmol) were added successively. The resulting mixture wasagain degassed with stream of nitrogen for 10 minutes. Then KOH (0.867g, 15.48 mmol) was added to the reaction mixture under nitrogenatmosphere. The resulting mixture was then heated to 100° C. and stirredfor 16 hours. After that the reaction mixture was cooled to 0° C.,quenched with water and washed with ethyl acetate (2×50 mL). The aqueousphase was then acidified with aqueous HCl (1.5 N, 5 mL) and extractedwith ethyl acetate (3×50 mL). The combined organic phase was washed withbrine solution (50 mL), dried over Na₂SO₄ and concentrated in vacuo toget compound XIb (crude) as a pale brown solid, which was taken for thenext step without any further purification. Yield: 1.0 g, 62.5%. LC_MS:Calc. for C₁₀H₉FN₂O₂ 208.19; Obs.: 209.0 [M+H]⁺.

Step 3: 8-(2,2-Diethoxyethoxy)-7-fluoro-1,3-dimethylquinoxalin-2(1H)-one(XIc)

To a stirred solution of compound XIb (1.0 g, 4.807 mmol) in dimethylsulfoxide (10 mL) at room temperature under nitrogen atmosphere wereadded cesium carbonate (2.34 g, 7.21 mmol) and bromoacetaldehyde diethylacetal (1.2 mL, 7.69 mmol successively. The resulting mixture was heatedto 90° C. and stirred for 16 hours. After that the reaction mixture wasdiluted with water (20 mL) and extracted with ethyl acetate (3×25 mL).The combined organic phase was washed with brine solution, dried overNa₂SO₄ and concentrated in vacuo. The obtained crude product was furtherpurified by column chromatography using silica gel (230-400 mesh)eluting with 15% ethyl acetate in petroleum ether to get compound XIc asa pale brown solid. Yield: 1.1 g, 73.33%. LC_MS: Calc. for C₁₆H₂₁FN₂O₄324.35; Obs.: 324.9 [M+H]⁺.

Step 4:2-((6-Fluoro-2,4-dimethyl-3-oxo-3,4-dihydroquinoxalin-5-yl)oxy)acetaldehyde(XI)

To a stirred solution of compound XIc (1.1 g, 3.39 mmol) indichloromethane (15 mL) at 0° C. under nitrogen atmosphere was addedtrifluoroacetic acid (5.5 mL, 5 volume) in dropwise. The resultingmixture was allowed to stir at room temperature for 2 hours. After thatthe reaction mixture was concentrated, basified with 10% NaHCO₃ solutionand extracted with dichloromethane (3×50 mL). The combined organic phasewas dried over Na₂SO₄ and concentrated in vacuo to get compound XI(crude) as a brown solid, which was used as such for the next stepwithout further purification. Yield: 0.4 g. LC_MS: Calc. for C₁₂H₁₁FN₂O₃250.23; Obs. 250.9 [M+H]+.

Synthesis of2-((3-Chloro-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridin-4-yl)oxy)acetaldehyde,(Intermediate XII)

Step 1: 3-Chloro-6-methoxy-1,5-naphthyridin-4-ol (XIIa)

To a stirred solution of 6-methoxy-1,5-naphthyridin-4-ol (10.0 g, 56.76mmol) in glacial acetic acid (150 mL) at room temperature under nitrogenatmosphere was added N-chlorosuccinimide (8.48 g, 63.57 mmol). Thereaction mixture was heated to 60° C. and stirred for 3 hour. Afterthat, the reaction mixture was cold to room temperature and solidprecipitated was filtered, washed with n-hexane and dried under vacuo toget compound XIIa as a white solid, which was used as such for the nextstep without any further purification. Yield: 10.0 g (crude), 85.03%.LC_MS Calc. for C₉H₇ClN₂O₂, 210.62; Obs: 211.0 [M⁺+H]; ¹H-NMR (300 MHz,DMSO-d₆): δ 8.40 (s, 1H) 7.99 (d, J=11.60 Hz, 1H), 7.20 (d, J=12.0 Hz,1H), 3.95 (s, 3H), 3.33 (brs, 1H).

Step2:10-Chloro-2,2-dimethyl-2,3-dihydro-5H-[1,4,2]oxazasilino[6,5,4-de][1,5]naphthyridin-5-one(XIIb)

To a stirred solution of compound XIIa (2.0 g, 9.49 mmol) in DMF (60 mL)at 0° C. under nitrogen atmosphere was added sodium hydride (0.57 g,14.24 mmol, 60% dispersed in mineral oil). The resulting mixture waswarmed to room temperature and stirred for 1 hour. Then chloro(chloromethyl)dimethylsilane (2.02 mL, 15.19 mmol) was added to thereaction mixture at room temperature and allowed to stir for another 1.5hour. The reaction mixture then heated to 100° C. and stirred for 16hours. After that, the reaction mixture was quenched with methanol (1mL) and concentrated completely in vacuo. The obtained crude product wastriturated with diethyl ether, filtered and dried under vacuo to getcompound XIIb as a pale orange solid, which was used as such for thenext step without any purification. Yield: 3.0 g (crude). LC_MS Calc.for C₁₁H₁₁ClN₂O₂Si, 266.76; Obs: 266.8; ¹H-NMR (400 MHz, DMSO-d₆): δ8.45 (s, 1H) 7.88 (d, J=9.60 Hz, 1H), 6.89 (d, J=9.60 Hz, 1H), 3.62 (s,2H), 0.47 (s, 6H).

Step 3: 7-Chloro-8-hydroxy-1-methyl-1,5-naphthyridin-2(1H)-one (XIIc)

To a stirred solution of compound XIIb (3.0 g, 11.27 mmol) in a mixtureof 1,4-dioxane/methanol (113 mL, 2:1) at room temperature under nitrogenatmosphere was added cesium fluoride (5.13 g, 33.82 mmol). The reactionmixture was then heated to 80° C. and stirred for 16 hours. After that,the reaction mixture was concentrated in vacuo. The residue obtained wasdissolved in water (5 mL) and neutralized with 1.5 N HCl (adjustedpH˜6-7). The solid precipitated out was filtered and dried under vacuoto get compound XIIc as an off white solid, which was used as such forthe next step without any purification. Yield: 2.0 g (crude). LC_MSCalc. for C₉H₇ClN₂O₂, 210.62; Obs.; 211.1; [M⁺+H]; ¹H-NMR (400 MHz,DMSO-d₆): δ 12.53 (brs, 1H), 8.29 (s, 1H), 7.69 (d, J=9.20 Hz, 1H), 6.84(d, J=9.60 Hz, 1H), 3.98 (s, 3H).

Step 4:7-Chloro-8-(2,2-diethoxyethoxy)-1-methyl-1,5-naphthyridin-2(1H)-one(XIId)

To a stirred solution of compound XIIc (0.5 g, 2.37 mmol) in DMSO (5 mL)at room temperature under nitrogen atmosphere were addedbromoacetaldehyde diethyl acetal (0.45 mL, 2.85 mmol) and cesiumcarbonate (1.16 g, 3.56 mmol) successively. Then the reaction mixturewas heated to 100° C. and stirred for 16 hours. After that, the reactionmixture quenched with water and extracted with ethyl acetate (3×50 mL).The combined organic phase was washed with brine solution (50 mL), driedover anhydrous sodium sulfate and concentrated in vacuo. The obtainedcrude product was further purified by column chromatography using silicagel (60-120 mesh) eluting with 30% ethyl acetate in petroleum ether toget compound XIId as a brown solid. Yield: 0.3 g, 38.34%. LC_MS Calc.for C₁₅H₁₉CN₂O₄, 326.78; Obs.; 327.1; [M⁺+H]; ¹H-NMR (400 MHz, DMSO-d₆):δ 8.34 (s, 1H), 8.08 (d, J=10.00 Hz, 1H), 6.86 (d, J=10.40 Hz, 1H), 4.74(s, 1H), 4.41 (d, J=4.80 Hz, 2H), 3.95 (s, 3H), 3.66-3.60 (m, 2H),3.47-3.40 (m, 2H), 1.03-1.00 (m, 6H).

Step 5:2-((3-Chloro-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridin-4-yl)oxy)acetaldehyde(XII)

To a stirred solution of compound 5 (0.3 g, 0.92 mmol) indichloromethane (3 mL) at 0° C. under nitrogen atmosphere were addedtrifluoroacetic acid (3 mL). The resulting mixture was then warmed toroom temperature and stirred for 3 hours. After that, the reactionmixture quenched with 10% NaHCO₃ solution and extracted with ethylacetate (3×20 mL). The combined organic phase was washed with brinesolution (20 mL), dried over anhydrous sodium sulfate and concentratedin vacuo to get compound 6 as a pale brown solid, which was used as suchfor the next step without any purification. Yield: 0.2 g (crude). LC_MSCalc. for C₁₁H₉CN₂O₃, 252.65; Obs: 250.8 [M⁺−H]; ¹H-NMR (300 MHz,DMSO-d₆): δ 9.62 (s, 1H), 8.28-8.24 (m, 1H) 8.02 (d, J=14.0 Hz, 1H),6.86-6.82 (m, 1H), 4.20-4.02 (m, 2H), 3.93 (s, 3H)

Further, the compounds of Formula I were prepared utilizing theintermediates above.

Synthesis of(S)-6-(5-(((2-((5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridin-4-yl)oxy)ethyl)amino)methyl)-2-oxooxazolidin-3-yl)-2H-pyrido[3,2-b][1,4]oxazin-3(4H)-one(Compound 1)

To a mixture of aldehyde, I (0.1 g, 0.45 mmol) and amine IV (0.12 g,0.45 mmol) in dry methanol (10 mL) and dry dichloromethane (10 mL) wasadded AcOH (0.10 mL) and allowed to stir for 16 hours at roomtemperature. To this was added cyanoborohydride resin (0.34 g, 0.68mmol) and stirred for another 15 minutes at room temperature. Thereaction mixture was filtered, and the filtrate was concentrated to getthe crude. The crude was purified by preparative HPLC to afford the pureproduct (Compound 1) as formate salt (off-white solid, 13 mg, 6%). LC-MSCalc. for C₂₂H₂₂N₆O₆: 466.45; Obs.: 467.2 [M⁺+H]; ¹H NMR (400 MHz,DMSO-D₆): δ 11.16 (s, 1H), 8.34 (m, 1H), 7.83 (d, J=8.4 Hz, 1H), 7.57(d, J=8.4, Hz, 1H), 7.38 (d, J=9 Hz, 1H), 7.21 (m, 1H), 6.82 (d, J=9.8Hz, 1H), 4.76 (brs, 1H), 4.62 (s, 2H), 4.23 (m, 2H), 4.13-4.11 (m, 1H),3.87 (m, 1H), 3.80 (s, 3H), 3.08 (m, 2H), 2.96 (m, 3H).

Synthesis of(S)-6-(5-(((2-((7-fluoro-1-methyl-2-oxo-1,2-dihydroquinolin-8-yl)oxy)ethyl)amino)methyl)-2-oxooxazolidin-3-yl)-2H-pyrazino[2,3-b][1,4]oxazin-3(4H)-one(Compound 2)

To a mixture of aldehyde I (0.2 g, 0.85 mmol) and amine VI (0.22 g, 0.85mmol) in dry MeOH (10 mL) and DCM (10 mL) was added AcOH (0.25 mL) andallowed to stir for 16 h. To this was added cyanoborohydride resin (2.05mmol %, 0.63 g, 1.27 mmol) and stirred for 5 min. The reaction mixturewas filtered, and the filtrate was concentrated to get the crudeproduct. The crude was purified by reverse phase preparative HPLC methodto afford the Compound 2 as off-white solid (Formate salt, 50 mg). LC-MSCalc. for C₂₂H₂₁FN₆O₆: 484.44; Obs.: 485.1; [M⁺+H]; ¹H NMR (400 MHz,DMSO-D₆): δ 8.39 (s, 1H), 8.23 (s, 1H), 7.85 (d, J=9.44 Hz, 1H),7.49-7.50 (m, 1H), 7.22 (t, J=10.08 Hz, 1H), 6.56 (d, J=9.36 Hz, 1H),4.79-4.81 (m, 3H), 4.03-4.04 (m, 3H), 3.83-3.85 (m, 5H), 2.93-2.94 (m,4H).

Synthesis of(R)-6-(5-(((2-((7-fluoro-1-methyl-2-oxo-1,2-dihydroquinolin-8-yl)oxy)ethyl)amino)methyl)-2-oxooxazolidin-3-yl)-2H-pyrazino[2,3-b][1,4]oxazin-3(4H)-one(Compound 3)

To a mixture of compound H (0.5 g, 1.88 mmol) and compound VI (0.443 g,1.88 mmol) in a mixture of dry MeOH (20 mL) and CH₂Cl₂(20 mL) at roomtemperature under nitrogen atmosphere were added AcOH (0.5 mL) followedby 2-picoline borane complex (2.05 mmol %) (0.120 g, 1.13 mmol). Thereaction mixture was continued to stir at room temperature for 1 hour.The reaction mixture was quenched with 1% HCOOH in water andconcentrated in vacuo to get the crude. The obtained crude was purifiedby column chromatography by eluting with 8-10% methanol indichloromethane. The pure product obtained was further triturated withdiethyl ether to afford Compound 3 as an off-white solid (Formate salt).Yield: 0.2 g, 21.95%. LC-MS Calc. for C₂₂H₂₁FN₆O₆: 484.44; Obs.: 485.1;[M⁺+H]; ¹H NMR (400 MHz, DMSO-d₆): δ 11.63 (S, 1H), 8.39 (s, 1H), 8.14(s, 1H), 7.87 (d, J=9.44 Hz, 1H), 7.54-7.51 (m, 1H), 7.24 (t, J=10.08Hz, 1H), 6.57 (d, J=9.20 Hz, 1H), 4.86-4.81 (m, 3H), 4.17-4.11 (m, 3H),3.88-3.83 (m, 4H), 3.33-3.11 (m, 4H). HPLC Purity=96.21%, Column:X-Bridge C8 (50×4.6) mm, 3.5 μm, Mobile Phase A: 0.1% TFA in water,Mobile Phase B: 0.1% TFA in acetonitrile.

Synthesis of6-((5S)-5-(((1-((7-fluoro-1-methyl-2-oxo-1,2-dihydroquinolin-8-yl)oxy)propan-2-yl)amino)methyl)-2-oxooxazolidin-3-yl)-2H-pyrazino[2,3-b][1,4]oxazin-3(4H)-one(Compound 4)

To a stirred mixture of compound X (260 mg, 1.0 mmol) and compound V(275 mg, 1.0 mmol) in a mixture of dry MeOH/dichloromethane (30 mL, 1:1)at room temperature under nitrogen atmosphere were added AcOH (0.6 mL)and 2-picoline-borane complex (110 mg, 1.0 mmol) successively. Thereaction mixture was continued to stir at room temperature for 16 hours.After that, the reaction mixture was quenched with 0.1% HCOOH in waterand concentrated under reduced pressure. The obtained crude product wasfurther purified by PREP HPLC to get Compound 4 as an off-white solid.Yield: 100 mg, 50.20%. LC_MS Calc. for C₂₃H₂₃FN₆O₆, 498.47; Obs.: 499.1[M⁺+H]. ¹H-NMR (300 MHz, DMSO-d₆): δ 11.60 (brs, 1H), 8.38-8.35 (m, 1H),7.85-7.82 (d, J=9.3 Hz, 1H), 7.52-7.47 (t, J=6.6 Hz, 1H), 7.24-7.18 (t,J=9.3 Hz, 1H), 6.57-6.53 (d, J=9.3 Hz, 1H), 4.84 (brs, 3H), 4.15-4.09(m, 1H), 3.95-3.85 (m, 2H), 3.80 (s, 3H), 3.19-3.04 (m, 4H), 1.17-1.14(d, 3H); HPLC Purity=99.25% (HPLC Column: XBridge C8 (50×4.6) mm, 3.5μm, Mobile Phase A: 0.1% TFA in water, Mobile Phase B: 0.1% TFA inAcetonitrile.

Synthesis of(S)-6-(5-(((2-((7-fluoro-1,4-dimethyl-2-oxo-1,2-dihydroquinolin-8-yl)oxy)ethyl)amino)methyl)-2-oxooxazolidin-3-yl)-2H-pyrazino[2,3-b][1,4]oxazin-3(4H)-one(Compound 5)

To a stirred mixture of compound IX (250 mg, 1.00 mmol) and compound V(280 mg, 1.00 mmol) in a mixture of dry MeOH/dichloromethane (20 mL,1:1) at room temperature under nitrogen atmosphere were added AcOH (0.5mL) and 2-picoline-borane complex (64 mg, 0.6024 mmol) successively. Thereaction mixture was continued stirred at room temperature for 1 hour.After that, the reaction mixture was quenched with 0.1% HCOOH in waterand concentrated under reduced pressure. The obtained crude product wasfurther purified by PREP HPLC to get Compound 5 as an off-white solid.Yield: 50 mg, 10.0%. LC_MS Calc. for C₂₄H₂₅FN₆O₆, 512.50; Obs.: 513.1[M⁺+H]; ¹H-NMR (400 MHz, DMSO-d₆): δ 11.65 (brs, 1H), 8.39 (s, 1H),7.62-7.58 (m, 1H), 7.31-7.26 (t, J=10.0 Hz, 1H), 6.54 (d, J=5.2 Hz, 1H),4.87-4.83 (m, 3H), 4.24-4.17 (m, 2H), 3.83 (s, 3H), 3.78-3.74 (m, 1H),2.98 (brs, 2H), 2.50 (s, 3H), 2.06 (brs, 2H); HPLC Purity=96.24% (HPLCColumn: Atlantis dC18 (250*4.6) mm 5 μm, Mobile Phase A: 0.1% TFA inwater, Mobile Phase B: Acetonitrile.

Synthesis of(S)-6-(5-(((2-((3-chloro-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridin-4-yl)oxy)ethyl)amino)methyl)-2-oxooxazolidin-3-yl)-2H-pyrazino[2,3-b][1,4]oxazin-3(4H)-one(Compound 6)

To a stirred solution of compound XII (0.2 g, 0.79 mmol) and compound V(0.232 g, 0.87 mmol) in a mixture of dry MeOH/dichloromethane (8 mL,1:1) at room temperature under nitrogen atmosphere was added AcOH (0.2mL) and allowed to stir for 10 mins. Then 2-picoline borane complex(0.051 g, 0.477 mmol) was added at 0° C. The reaction mixture was thenwarmed to room temperature and stirred for 3 hours. After that thereaction mixture was quenched with 1% formic acid in water andconcentrated in vacuo. The obtained crude product was further purifiedby PREP HPLC (reverse phase) to get Compound 6 as a white solid (Formatesalt). Yield: 0.010 g. LC_MS Calc. for C₂₁H₂₀ClN₇O₆, 501.88; Obs.: 502.2[M⁺+H]⁺.

Synthesis of((S)-6-(5-(((2-((6-fluoro-4-methyl-3-oxo-3,4-dihydroquinoxalin-5-yl)oxy)ethyl)amino)methyl)-2-oxooxazolidin-3-yl)-2H-pyrazino[2,3-b][1,4]oxazin-3(4H)-one(Compound 7)

To a stirred solution of compound VII (0.15 g, 0.635 mmol) and compoundV (0.17 g, 0.635 mmol) in a mixture of dry methanol/dichloromethane (40mL, 1:1) at room temperature under nitrogen atmosphere were added AcOH(0.3 mL) and Pic-BH₃ (32 mg, 0.38 mmol). The resulting mixture wascontinued to stir at room temperature for 1 hour. The progress of thereaction was monitored by TLC. After that the reaction mixture wasquenched with water (3 mL) and concentrated under reduced pressure. Theobtained crude product was further purified by column chromatographyusing silica gel (230-400 mesh) eluting with 5% Metanol in DCM to getcompound 7a as a brown solid. Yield: 0.12 g, 38.7%. LC_MS: Calc. forC₂₁H₂₂FN₇O₆ 487.45; Obs.: 486.3 [M−H]⁺.

To a stirred solution of compound 7a (0.12 g, 0.2462 mmol) in 1,4-dioxane (4 mL) at room temperature under nitrogen atmosphere was addedMnO₂ (12 mg, 0.1478 mmol) at once. The resulting mixture was heated to100° C. and stirred for 2 hours. After that the reaction mixture wascooled to room temperature, filtered through celite pad and thoroughlywashed with ethyl acetate and DCM (1:1). The combined filtrate wasconcentrated under reduced pressure to get crude compound as a palebrown solid, which was further purified by PREP HPLC to get compoundCompound 7 as trifluoro acetic acid salt: Off white amorphous powder;Yield: 50 mg, 420%.

LC_MS: Calc. for C₂₁H₂OFN₇O₆ 485.43; Obs.: 486.1 [M+H]⁺; ¹H-NMR (400MHz, DMSO-d₆): δ 11.68 (s, 1H), 9.32 (bs, 2H), 8.40 (s, 1H), 8.23 (s,1H), 7.71-7.68 (m, 1H), 7.44-7.39 (t, J=9.32 Hz, 1H), 5.13 (bs, 1H),4.89 (s, 2H), 4.35-4.34 (m, 2H), 4.26-4.24 (m, 1H), 3.86 (s, 3H),3.84-3.82 (m, 1H), 3.55-3.51 (m, 4H). LC_MS: Calc. for C₂₁H₂OFN₇O₆485.43; Obs.: 486.1 [M+H]+; HPLC: 1.95 min; 98.77%; HPLC Column:X-Bridge C8 (50×4.6) mm, 3.5 μm, Mobile Phase A: 0.1% TFA in H₂O, MobilePhase B: Acetonitrile.

Synthesis of((R)-6-(5-(((2-((6-fluoro-4-methyl-3-oxo-3,4-dihydroquinoxalin-5-yl)oxy)ethyl)amino)methyl)-2-oxooxazolidin-3-yl)-2H-pyrazino[2,3-b][1,4]oxazin-3(4H)-one(Compound 8)

To a stirred solution of compound VIII (0.250 g, 1.06 mmol) and compoundVI (0.280 g, 1.06 mmol) in a mixture of dry MeOH/dichloromethane (20 mL,1:1) at room temperature under nitrogen atmosphere was added AcOH (0.5mL) and allowed to stir for 10 mins. The reaction mixture was cold to 0°C. and was added 2-picoline borane complex (0.067 g, 0.63 mmol). Thereaction mixture was then warmed to room temperature and stirred for 3hours. After that the reaction mixture was quenched with water andconcentrated in vacuo. The obtained crude product was purified by columnchromatography using silica gel (60-120 mesh) eluting with 4% ofmethanol in dichloromethane to get compound 8a. Yield: 0.150 g, 30.91%;LC_MS Calc. for C₂₁H₂₂FN₇O₆, 487.45; Obs.: 487.8 [M⁺+H].

To a stirred solution of compound 8a (0.150 g, 0.307 mmol) in 1,4-dioxane (3 mL) at room temperature under nitrogen atmosphere was addedMnO₂ (0.192 g, 2.15 mmol). The reaction mixture was then heated to 100°C. and stirred for 2 hours. After that, the reaction mixture wasfiltered through celite, washed with dichloromethane/methanol (100 mL,1:1) and concentrated in vacuo. The obtained crude product was purifiedby PRPE HPLC (reverse phase) to get Compound 8 as formate salt; Whiteamorphous powder; Yield: 0.020 g, 13.29%.

LC_MS Calc. for C₂₁H₂₀FN₇O₆, 485.43; Obs.: 483.9 [M⁺−H]; ¹H-NMR (400MHz, DMSO-d₆): δ 8.36 (s, 2H), 8.15 (s, 1H), 7.61-7.58 (m, 1H),7.34-7.30 (m, 1H), 4.84 (s, 2H), 4.81-4.78 (m, 1H), 4.12-4.4.07 (m, 3H),3.86-3.82 (m, 4H), 3.00-2.97 (m, 2H), 2.94-2.89 (m, 2H). HPLCPurity=91.42%, Column: X-Bridge C8 (50×4.6) mm, 3.5 μm, Mobile Phase A:0.1% TFA in water, Mobile Phase B: Acetonitrile.

Synthesis of(S)-6-(5-(((2-((6-fluoro-2,4-dimethyl-3-oxo-3,4-dihydroquinoxalin-5-yl)oxy)ethyl)amino)methyl)-2-oxooxazolidin-3-yl)-2H-pyrazino[2,3-b][1,4]oxazin-3(4H)-one(Compound 9)

To a stirred mixture of compound XI (0.2 g, 0.8 mmol) and compound V(210 mg, 0.8 mmol) in a mixture of dry MeOH/dichloromethane (30 mL, 1:1)at room temperature under nitrogen atmosphere were added AcOH (0.4 mL)and 2-picoline-borane complex (51 mg, 0.48 mmol). The reaction mixturewas continued to stir at room temperature for 1 hour. After that, thereaction mixture was quenched with 0.1% HCOOH in water and concentratedunder reduced pressure. The obtained crude product was further purifiedby PREP HPLC to get Compound 9 as an off-white solid as a trifluoroacetic acid salt. Yield: 50 mg, 12.82%. LC_MS Calc. for C₂₂H₂₂FN₇O₆,499.46; Obs.: 500.0 [M⁺+H]; ¹H NMR (400 MHz, DMSO-d₆): δ 11.69 (brs,1H), 9.32 (brs, 2H), 8.40 (s, 1H) 7.62-7.58 (m, 1H), 7.39-7.34 (m, 1H),5.16-5.12 (m, 1H), 4.89 (s, 2H), 4.36-4.24 (m, 2H), 3.87 (s, 3H),3.85-3.83 (m, 2H), 3.57-3.52 (m, 4H), 2.33 (s, 3H); HPLC Purity=97.03%(HPLC Column: X-Bridge C8(50×4.6) mm, 3.51 μm, Mobile Phase A: 0.1% TFAin water, Mobile Phase B: Acetonitrile.

Synthesis of(S)-5-(((2-((6-fluoro-4-methyl-3-oxo-3,4-dihydroquinoxalin-5-yl)oxy)ethyl)amino)methyl)-3-(3-oxo-3,4-dihydro-2H-pyrazino[2,3-b][1,4]thiazin-6-yl)oxazolidin-2-one(Compound 10)

To a stirred solution of compound VIII (0.150 g, 0.63 mmol) and compoundVII (0.179 g, 0.63 mmol) in a mixture of dry MeOH/dichloromethane (12mL, 1:1) at room temperature under nitrogen atmosphere was added AcOH(0.3 mL) and allowed to stir for 10 mins. Then 2-picoline borane complex(0.040 g, 0.38 mmol) was added at 0° C. The resulting mixture was warmedto room temperature and stirred for 3 hours. After that the reactionmixture was quenched with water and concentrated in vacuo. The obtainedcrude product was purified by column chromatography using silica gel(60-120 mesh) eluting with 5% of methanol in dichloromethane to getcompound 10a. Yield: 0.1 g, 31.65%; LC_MS Calc. for C₂₁H₂₂FN₇O₅S 503.51;Obs.: 504.1 [M⁺+H]⁺.

To a stirred solution of compound 10a (0.1 g, 0.198 mmol) in 1,4-dioxane (2 mL) at room temperature under nitrogen atmosphere was addedmanganese dioxide (0.124 g, 1.39 mmol). The reaction mixture was thenheated to 100° C. and stirred for 2 hours. After that, the reactionmixture was filtered through celite pad, washed withdichloromethane/methanol (1:1, 100 mL) and concentrated in vacuo. Theobtained crude product was purified further by PRPE HPLC (reverse phase)to get Compound 10 as formate salt. White amorphous powder: Yield: 0.020g, 20.14%. LC_MS Calc. for C₂₁H₂₀FN₇O₅S 501.49; Obs.: 499.8 [M⁺−H]; ¹HNMR (400 MHz, DMSO-d₆): δ 11.96 (brs, 1H), 8.78 (s, 1H), 8.30 (bs, 1H),8.15 (s, 1H), 7.61-7.57 (m, 1H), 7.34-7.29 (m, 1H), 4.84-4.80 (m, 1H),4.12-4.4.07 (m, 3H), 3.86-3.82 (m, 4H), 3.76 (s, 2H), 2.98-2.91 (m, 4H);HPLC Purity=99.55%, Column: X-Bridge C8 (50×4.6) mm, 3.5 μm, MobilePhase A: 0.1% TFA in water, Mobile Phase B: Acetonitrile.

Example 3

Biological Activity

Antibacterial Activity:

The compounds of Formula I are of interest due to their potentantibacterial effects. The ability of the compounds of the presentdisclosure as disclosed herein, to achieve an antibacterial effect maybe evaluated with regards to their ability to inhibit the growth ofbacterial species like Escherichia coli ATCC 25922, Staphylococcusaureus ATCC 29213, Klebsiella pneumoniae ATCC 13883, Acinetobacterbaumannii ATCC 19606, Pseudomonas aeruginosa ATCC 27853, Enterococcusfaecalis ATCC 29212, Enterococcus faecalis ATCC 29212, Proteus mirabilisATCC 43071, Enterobacter cloacae ATCC 13047, Citrobacter freundii ATCC43864 and Morganella morganii ATCC 25830 using an assay based on thefollowing Minimum Inhibitory Concentration (MIC) protocol.

The test bacteria were grown in Luria Bertani Broth (HIMEDIA M1245), 25grams of the powder was dissolved in 1000 ml distilled water andsterilized by autoclaving at 15 lbs pressure (121° C.) for 20 minutes.The medium sterility was checked by incubating at 37° C. for a period of48 h.

Bacterial cultures that were stored as glycerol stocks at −80° C. weresub cultured on LB agar plates to obtain isolated colonies. A singlecolony of each strain was cultured in LB broth. The cultures wereincubated at 37° C., 200 rpm till they reach an optical density (OD at600 nm) of 0.8 to 1. This log phase culture was diluted in LB broth to acell number of 5-8×10{circumflex over ( )}5 CFU/mL to be used asinoculum for MIC experiments. Test compounds were dissolved in dimethylsulfoxide (DMSO) to a stock concentration of 4 mg/ml. A two-folddilution series of this DMSO stock was prepared in a 96 well V bottommicrotitre plate from rows A to H. A 3 μL volume of these dilutions weretransferred to a 96-well flat bottom microtitre assay plate. Controls tomonitor the effects of DMSO and media sterility were included. Each wellwas inoculated with 150 μL of the above diluted culture. The plates wereincubated at 37° C. overnight in a humidified incubator. The followingmorning, the plates were read using a Spectrophotometer at 600 nMwavelength.

Minimum Inhibitory Concentration (MIC) is defined as the lowest drugconcentration containing well that shows 90% inhibition of bacterialgrowth. The antibacterial activity (MIC) determined againstrepresentative Gram-positive (Staphylococcus aureus ATCC 29213,Enterococcus faecalis ATCC 29212) and Gram-negative (Escherichia coliATCC25922, Klebsiella pneumoniae ATCC 13883, Acinetobacter baumanniiATCC 19606, Pseudomonas aeruginosa ATCC 27853, Proteus mirabilis ATCC43071, Enterobacter cloacae ATCC 13047, Citrobacter freundii ATCC 43864,Morganella morganii ATCC 25830) pathogen were reported in Table 1. Theexemplified compounds belonging to Formula I demonstrated potentantibacterial activity both Gram-positive and Gram-negative pathogens.

TABLE 1 MIC studies in LB Media Minimum Inhibitory Concentration (μg/mL)in LB Media Compound S. au E. fa E. co P. ae K. pn A. ba C. fr E. cl M.mo P. mi 1 0.25 1 0.5 4 1 2 1 8 2 16 2 ≤0.015 0.06 0.03 0.5 0.06 0.06≤0.03 0.125 0.125 0.125 3 0.015 0.06 0.06 0.5 0.06 0.06 0.06 0.125 0.030.125 4 0.06 0.125 0.25 2 0.25 0.25 0.5 0.5 1 2 5 0.125 0.125 0.06 10.25 0.25 ND ND ND ND 6 >4 >4 >4 >4 >4 >4 >4 >4 >4 >4 7 ≤0.015 0.06 0.030.25 0.06 0.06 0.06 0.125 0.06 0.25 8 ≤0.015 0.06 0.03 0.5 0.06 0.060.06 0.125 0.03 0.25 9 ≤0.06 0.25 0.125 4 0.5 0.125 0.25 1 0.5 2 10≤0.003 0.025 0.025 0.25 0.025 0.013 0.025 0.05 0.025 0.125 Cifro- 0.40.4 0.012 0.1 0.05 0.4 ≤0.006 0.0125 ≤0.006 0.025 floxacin S. au: S.aureus ATCC 29213; E. fa: E. faecalis ATCC 29212; E. co: E. coli ATCC25922; P. ae: P. aurigenosa ATCC 27853; K. pn: K. pneumoniae ATCC 13883;A. ba: A. baumannii ATCC 19606; C. fr: Citrobacter freundii ATCC 43864;E. cl: Enterobacter cloacae ATCC 13047; M. mo: Morganella morganii ATCC25830; P. mi; Proteus mirabilis ATCC 43071Enzyme Inhibition Assay: Determination IC₅₀ Value Against E. coli GyraseSupercoiling and E. coli Topo IV Decatenation

The compounds of Formula I or its stereoisomers, pharmaceuticallyacceptable salts, complexes, hydrates, solvates, tautomers, polymorphs,racemic mixtures, optically active forms and pharmaceutically activederivative thereof, were evaluated for use in killing or inhibiting thegrowth of Gram-positive and Gram-negative bacteria through inhibition ofbacterial Type II topoisomerases namely, DNA gyrase and Topo IV. Thepresent disclosure also provides evidence for treating infection causedboth Gram-positive and Gram-negative bacteria through the inhibition ofbacterial topoisomerases using E. coli, DNA gyrase and Topo IV enzymes.

Procedure for E. coli DNA Gyrase Supercoiling Assay

E. coli gyrase supercoiling and its inhibition was assayed using a kitprocured from Inpiralis (K₀₀₀₁) and the protocol (PMID: 2172086) wasadapted with necessary modifications. The compounds to be tested wereincubated for 10 min with 2.5 nM of E. coli DNA gyrase in a 30 μl volumereaction and 3.2% DMSO. The reactions were then started with theaddition of 60 ng relaxed pBR322 plasmid DNA and continued for 45 min at37° C. The reaction mixture contained 35 mM Tris.HCl (pH 7.5), 24 mMKCl, 1.8 mM spermidine, 4 mM MgCl₂, 2 mM DTT, 6.5% (w/v) glycerol, 0.1mg/mL BSA, and 1 mM ATP. The reaction was then stopped by addition of0.75 μL of Proteinase K (20 mg/mL) and 3 μL of 2% SDS and furtherincubated at 37° C. for 30 min. This was followed by the addition of 4μL of STEB (40% (w/v) sucrose, 100 mM Tris-HCl pH 8, 1 mM EDTA, 0.5mg/ml Bromophenol Blue) and the supercoiled/relaxed forms of plasmid DNAwere separated by agarose gel electrophoresis. The 1% agarose gels wererun for 3 h at 4 V/cm in 1×TAE (40 mM Tris, 20 mM acetic acid, 1 mMEDTA). To visualize the DNA the gels were stained for 10 min with 0.7μg/mL ethidium bromide and excess dye was removed by several washes withwater. IC₅₀ values were determined by quantifying the supercoiled andrelaxed DNA in each of the reactions from a gel image by a densitometricmethod using the Quantity One Software (Bio-rad).

Procedure for E. coli Topoisomerase IV Decatenation Assay

E. coli topoisomerase IV decatenation activity and its inhibition wasassayed using a kit procured from Inpiralis (D4002) and the kit protocolwas adapted with necessary modifications similar to the gyrasesupercoiling assays. The compounds to be tested were incubated for 10minutes with 5 nM of E. coli topoisomerase IV in a 30 μl volume reactionand 3.2% DMSO. The reactions were started with the addition of 60 ng ofkDNA and continued for 40 min at 37° C. The final reaction mixturecontains 40 mM Tris-HCl (pH 7.6), 100 mM potassium glutamate, 10 mMmagnesium acetate, 10 mM DTT, 1 mM ATP, and 50 μg/ml albumin. Thereactions were stopped by addition of 0.75 μL of Proteinase K (20 mg/mL)and 3 μL of 2% SDS and further incubated at 37° C. for 30 min. This wasfollowed by the addition of 4 μL of STEB (40% (w/v) sucrose, 100 mMTris-HCl pH 8, 1 mM EDTA, 0.5 mg/ml Bromophenol Blue) and thekDNA/minicircles forms were separated by agarose gel electrophoresis.The 1% agarose gels were run for 3 h at 4V/cm in 1×TAE (40 mM Tris, 20mM acetic acid, 1 mM EDTA). To visualize the DNA, the gels were stainedfor 10 min with 0.7 μg/mL ethidium bromide and excess dye was removed byseveral washes with water. IC_(50S) were determined by quantifying theKinetoplast DNA (kDNA) band inside the gel well and decatenatedminicircles that migrate into the gel in each of the reactions from agel image by a densitometric method using the Quantity One Software(Bio-rad).

Representing compounds of Formula I were evaluated against of E. coliDNA gyrase and Topo IV enzyme using gel based supercoiling assay forgyrase inhibition and decatenation assay for Topo IV inhibition. Theresults of bacterial Type II Topo isomerases (Gyrase and Topo IV) havebeen presented in the Table 2 below.

The results presented in the Table 2 indicate that the compounds ofFormula I exerts antibacterial activity through inhibition bacterialtype II topoisomerase activity and signifies the dual mode of bacterialtopoisomerases (Gyrase and Topo IV) inhibition for observedantibacterial activity of the compounds.

TABLE 2 Evaluation of compounds of Formula I against of E. coli DNAgyrase and Topo IV enzyme Compound E. coli DNA Gyrase IC50 (μM) E. coliTopo IV IC50 (μM) 1 <0.250 <0.250 2 0.012 0.045 3 0.011 ND 4 0.03 <0.3505 0.033 <0.187 6 6.33 17.70 7 0.015 <0.220 9 0.04 ND 10 0.022 <0.370Ciprofloxacin 0.233 14.4

The IC₅₀ values for majority of the compounds belonging to Formula I wasfound to be ≤0.250 for both E. coli DNA Gyrase and E. coli Topo IV. Onthe other hand, IC₅₀ values for Compound 2 was found to be ≤0.05 forboth the enzymes. This denotes that compounds of Formula I exert theirantibacterial activity through inhibition of bacterial topoisomerases(Gyrase and Topo IV enzymes) inside the bacterial cell.

In order to test the ability of compounds to retain the antibacterialactivity against clinical strains of bacteria, antibacterialsusceptibility studies (MIC₅₀ and MIC₉₀ determination) were carried fora representative compound (Compound 2) from the series using clinicalstrains of five Gram-negative bacterial species (E. coli, P. aurigenosa,K. pneumoniae, A. baumanni, E. cloacae) according the standard CLSIguidelines and the results are presented Table 3 below. The standarddrugs ciprofloxacin and meropenem were used as positive controls in thestudy.

TABLE 3 Susceptibility (MIC₅₀ and MIC₉₀ determination) studies E. coliCiprofloxacin Meropenem Compound 2 Number of strain 201 201 176ATCC25922 0.015 0.06 0.03 Minimum 0.015 0.03 0.03 MIC₅₀ (μg/ml) 16 0.060.25 MIC₉₀ (μg/ml) 16 4 0.25 Aba Ciprofloxacin Meropenem Compound 2Number of strain 169 169 132 ATCC19606 0.5 0.5 0.06 Minimum 0.06 0.031250.03 MIC₅₀ (μg/ml) 16 8 0.06 MIC₉₀ (μg/ml) 16 32 0.25 Kpn CiprofloxacinMeropenem Compound 2 Number of strain 211 211 88 ATCC13883 0.03 0.060.06 Minimum 0.015 0.03 0.06 MIC₅₀ (μg/ml) 4 1 0.125 MIC₉₀ (μg/ml) 16 160.5 Pae Ciprofloxacin Meropenem Compound 2 Number of strain 215 215 176ATCC27853 0.25 0.5 0.5 Minimum 0.015 0.03 0.031 MIC₅₀ (μg/ml) 0.125 2 1MIC₉₀ (μg/ml) 16 8 1 E. cloacae Ciprofloxacin Meropenem Compound 2Number of strain 88 88 88 Minimum 0.06 0.06 0.03 MIC₅₀ (μg/ml) 0.06 0.250.125 MIC₉₀ (μg/ml) 16 16 0.25

The antibacterial susceptibility studies illustrated in the Table 3indicates that compounds of Formula I work against both drug sensitiveand resistant clinical strains of gram-negative bacterial species andretain the antibacterial activity. The MIC₉₀ values of Compound 2 are0.25 to 1 μg/ml range for 5 bacterial species and it is found to besuperior in comparison to standard drugs used in the study.

hERG Inhibition Assay

To test if the compounds of the present disclosure have any safety riskby inhibiting cardiac ion channel, particularly the potassium channel(Kr, hERG), compounds were tested using electrophysiological assays toevaluate its potential activity on hERG ion channel. The compounds weretested for inhibition of the human ether a go-go related gene (hERG) K+channel using QPatch HTX automated electrophysiology. 6-Pointconcentration-response curves were generated using three-fold serialdilutions from a maximum final test concentration of 300 μM and theresults are presented in table 4.

Compounds of Formula I were solubilised to 100 mM in DMSO beforedilution in HBPS to 300 μM. 6-Point concentration-response curves weregenerated using 3.16-fold serial dilutions from the top testconcentration.

Procedure:

Electrophysiological recordings were made from a Chinese Hamster Ovarycell line stably expressing the full-length hERG potassium channel.Single cell ionic currents were measured in whole-cell patch clampconfiguration at room temperature (21-23° C.) using the QPatch HTXplatform (Sophion). Intracellular solution contained (mM): 120 KF, 20KCl, 10 EGTA, 10 HEPES and was buffered to pH 7.3. The extracellularsolution (HEPES-buffered physiological saline, HBPS) contained (mM): 145NaCl, 4 KCl, 2 CaCl₂), 1 MgCl₂, 10 HEPES, 10 glucose, buffered to pH7.4.Cells were clamped at a holding potential of −80 mV. Cells were steppedto +20 mV for 2 s then −40 mV for 3 s before returning to the holdingpotential. This sweep was repeated 10 times at 10 s intervals. hERGcurrents were measured from the tail step and referenced to the holdingcurrent. Compounds were then incubated for 2 minutes prior to a secondmeasurement of ion channel current using an identical pulse train.

TABLE 4 hERG IC₅₀ values Compound hERG IC₅₀ (μM) 1 >100 2 124 3 25 4 365 71 7 >300 8 58 10 19 Cisapride 0.15Intravenous Formulation of Compound 2 for Pharmacokinetic (PK) Studies

Compound 2 was formulated in 10% L-Ascorbic acid solution in water toachieve the desirable solubility for intravenous route of administrationand adjusted to pH 4 by 1N NaOH.

Procedure: Weighed appropriate amount of the Compound 2 to be tested anddissolved in 1 ml of the 10% ascorbic acid solution. (Vortex for a fewseconds if the compound doesn't dissolve instantly). Sonicated thecompound solution at 37° C. for 5 minutes using a bath sonicator toobtain a visually clear solution. The above prepared solution was pHadjusted to pH˜4 with 1N NaOH solution (w/v) with sonication (finalFormulation pH˜4). The details of the Formulation solubility of Compound2 is given in the Table 5.

TABLE 5 IV Formulation solubility Solubility in 10% L-ascorbic acidFormulation in fresh MilliQ water(v/v), Final Composition pH~2.8Compound 2 15 mg/ml 15% L-Ascorbic acid Water for injection or FreshMiliQ water 1N NaOH solution for pH adjustment

The prepared IV formulation of Compound 2 were observed to be stable atroom temperature for more than 24 hours.

In Vivo Pharmacokinetic (PK) Studies in Rats

The rat pharmacokinetic studies were carried out in Sprague-Dawley (SD)rats to estimate the plasma clearance, volume of distribution, terminalhalf-life and oral bioavailability of Compound 2 following 1 hrintravenous infusion (IV) and oral gavge.

The Compound 2 exhibited moderate clearance, low volume of distributionand moderate half life and good oral bioavailability in SD rats. Doseproportional increase in AUC and Cmax was observed during IV infusionand Oral dosing of Compound 2 at 5, 10, 30 & 100 mg/kg doses in SD rats.This study suggest that the Compound 2 has desirable pharmacokineticprofile to keep blood levels of the parent above the MICs to demonstrateefficacy in rat infection models by IV infusion administration.

Procedure: The objective of this study was to investigate thepharmacokinetic profile of Example 12, following single ascending dosesvia intravenous (IV) constant rate infusion for 1 h, in male SpragueDawley rats. The study was performed using the following study design(n=3/group). For Oral dosing, Rats were dosed orally by gavage needle.The required dose volume of the appropriate test formulations were takenin a graduated syringe and administered slowly. Overnight fasted animalswere used for dosing and feed was provided 4 hr post dosing. Thepharmacokinetic experimental design for Compound 2 is tabulated in theTable 6 below:

TABLE 6 Pharmacokinetic experimental design for Compound 2 InfusionConc. in rate Dose No. of Dose formulation (mL/ Volume FormulationTreatment Group Route animals (mg/kg) (mg/mL) min/Kg) (mL/kg) vehicle G1G1 to 3 5 0.5 0.167 10 10% L-ascorbic G2 G4 3 30 3 mL/kg acid solutionin G3 IV 3 100 10 for IV water for injection G4 [Infusion] 3 150 15infusion and adjusted to pH4 G5 G5 to 3 30 3 by using 1N NaOH G6 G7 3100 10 15% L-ascorbic G7 PO 3 300 30 acid solution in water forinjection used for 150 mg/kg PK Tween80: 2% HPMC in water (1:99 v/v) fororal gavage

Serial blood sampling was used for blood collection. Blood samples werecollected at pre-dose, 0.25, 0.5 h (during infusion), 1 h (end ofinfusion) and 0.033, 0.25, 0.5, 1, 2, 4, 8 and 24 h, post infusion. Ateach time point about 100 μL of blood was collected from the jugularvein into a labeled microfuge tube containing 200 mM K₂EDTA solution (20μL per mL of blood) and equivalent volume of heparinized saline wasreplaced following sample collection. The blood samples were processedto obtain the plasma samples within 30 min of scheduled sampling time.All plasma samples were stored below −60° C. until bioanalysis.

Plasma samples were analyzed for Compound 2 using a fit-for purposeLC-MS/MS method with a lower limit of quantification (LLOQ) of 8.1ng/mL. The pharmacokinetic parameters of Compound 2 were calculatedusing the non-compartmental analysis tool of validated Phoenix®WinNonlin® software (version 6.4) with linear up and log down method forestimating AUC.

Male Sprague Dawley rats (8-12 weeks of age, weighing 280±20 g at thetime of dosing) used in the study were obtained from Invigo Researchlaboratories, USA. Anesthetic solution (Ketamine and xylazine) wasprepared by mixing 2 mL of Ketamine (50 mg/mL) with 0.5 mL of Xylazine(20 mg/mL). Rats were anaesthetized by ketamine and xylaxine solution byintra-peritoneal route at 1 mL/kg dose. The jugular and femoral veins ofrat were cannulated, and the study was performed 48 h post cannulation.All animals were fasted overnight before dose administration and foodwas provided 4 h post dose administration. All animals received water adlibitum during the study period. The IV and Oral pharmacokinetic profileCompound 2 presented in Table 7.

TABLE 7 Pharmacokinetic profile Compound 2 Parameter 5 mg/kg, IV 30mg/kg, IV 100 mg/kg, IV 150 mg/kg, IV C_(max)  2.8 ± 0.97 25.17 ± 0.6193.44 ± 4.4  111.8 ± 7.58 (μg/ml) T_(max) (h) 0.76 ± 0.02  1.0 ± 0.0 1.0 ± 0.0    2 ± 0.0 AUC_(inf)(h* 1.87 ± 0.35 21.80 ± 0.15 118.1 ± 13.6172.18 ± 10.74 μg/ml) AUC_(last) 1.87 ± 0.35 21.78 ± 0.15 118.0 ± 13.6 172.1 ± 10.75 (h*μg/ml) Vd (L/kg)  6.4 ± 1.07  4.94 ± 1.8  5.57 ± 0.56 5.38 ± 1.1 CLp 2.74 ± 0.52  1.38 ± 0.1  0.85 ± 0.1  0.87 ± 0.06(L/h/kg) Vss (L/kg) 1.09 ± 0.13  0.62 ± 0.05  0.69 ± 0.02  0.73 ± 0.07t_(1/2) (h) 1.53 ± 0.07  2.45 ± 0.78  4.53 ± 0.12  4.24 ± 0.67 10 mg/kg30 mg/kg, 100 mg/kg, 300 mg/kg, Parameter PO PO PO PO C_(max) 2.58 ±0.075  8.50 ± 2.4  9.79 ± 1.1  11.11 ± 3.1 (μg/ml) T_(max) (h) 0.25 ± 0 0.5 ± 0  0.33 ± 0.14   1.0 ± 0 AUC_(inf) 1.24 ± 0.1  7.54 ± 1.62 14.39± 4.6  27.24 ± 17.5 (h*μg/ml) Bioavail- 33.3 ± 3.1  66.8 ± 14.4  38.4 ±12.4  24.23 ± 15.6 ability* (F, %) t_(1/2) (h) 1.84 ± 0.15  1.70 ± 0.5 5.32 ± 2.1 2.2 *5 mg/kg IV infusion PK AUC used for calculating theoral bioavaiability

In Vivo Efficacy of Compound 2 in Rat Infection Models: In Vivo Efficacyin Rat Thigh E. coli and K. pneumoniae Model:

Compound 2 was tested in rat thigh infection model following intravenousinfusion of compound at doses of 100 mg/kg once, 30 mg/kg once dailyover a period of 1 hr to assess its efficacy. This study was performedfollowing all ethical practices as laid down in the guidelines foranimal care (Registration number No. 1852/PO/Rc/S/16/CPCSEA). The studywas approved by the Institutional Animals Ethics Committee (IAEC) of thetest facility. The formulation used was 10% of L-ascorbic acid in freshMilliQ water (w/v) with pH adjusted to 4.0 with 1N NaOH. On Day-4 (4days prior to the desired date of infection), each rat was dosed with asingle intra-peritoneal injection of cyclophosphamide equivalent to 150mg/kg and returned to its cage. On Day-1 (a day prior to infection) eachrat received a dose equivalent to 100 mg/kg of Cyclophosphamide. Thisprocedure ensured that animals will be neutropenic on day 0. On the dayof the infection, the overnight culture of the appropriatemicroorganisms [E. coli [ATCC25922]/A. baumannii [ATCC19606]/K.pneumoniae [ATCC13883] was adjusted to 1 OD [equal to ˜109 CFU/mL],centrifuged and the cells pelleted. The pelleted cells were suspended insterile normal saline to obtain 107 CFU/ml and used for infection. Theinoculum was serially diluted ten-fold in sterile CSDB broth and 0.05 mlof six dilutions were plated onto CSDA agar plates to determine theviable count (CFU/ml) of inoculum. All animals were divided intodifferent groups as specified in the experimental design for eachmicroorganism. All infections were conducted in a biological safetycabinet, with appropriate personnel protection. Infection was done byinjecting 0.2 ml of inoculum [approximately 1×107 CFU/ml in broth] ofthe appropriate microorganism using a 1.0 ml syringe and needle,post-laterally into the right thigh of the animal [approximately 2×106CFU/thigh]. A gentle shaking/mixing of inoculum between two animals wasfollowed for uniform distribution.

Two hours post infection, animals in groups 4, 5 and 6 were administeredintravenously with Compound 2, as a constant rate infusion (duration ofinfusion 1 h), under Ketamine 60 mg/kg IP+Xylazine 10 mg/kg IPanesthesia, at a dose volume of 10 ml/kg, at the rate of 0.16 ml/min.The dose levels of Compound 2 were 10, 30 and 100 mg/kg. Ciprofloxacin[10 mg/kg] and vehicle [10% of L-ascorbic acid in fresh MilliQ water(w/v) with pH adjustment [to pH˜4.0] with 1N Sodium hydroxide solution(w/v)] were dosed intravenously as single bolus doses. The totalduration of the study was 10 h.

Animals were sacrificed 10 hr post infection and thigh tissues wereharvested to enumerate the bacterial CFU count. Thigh muscles wereaseptically excised, weighed, and placed into 1 ml of sterile CSDBbroth, and homogenized (Omni Tip (220 V hand held)). Serial ten-folddilutions of the thigh homogenates were prepared in sterile lactosebroth and 0.05 mL of four dilutions for each thigh was plated onto CSDAagar plates. Bacterial colonies were enumerated following overnightincubation at 370 C. Bacterial densities were estimated as Log 10CFU/gram thigh. The Mean±SD Log 10 CFU/gram thigh was estimated in eachgroup. Significant differences between group means and control will beanalyzed by One-way ANOVA, followed by a Dunnett's multiple comparisontest, using Graphpad Prism at 95% confidence levels. A P value of <0.05was considered as significant. The results of the efficacy study arepresented in Table 8.

TABLE 8 Efficacy of Compound 2 against E. coli [ATCC25922] in aNeutropenic Thigh Infection Model in Rat Mean Log 10 CFU/ MEAN ± SDthigh reduction (Log₁₀ CFU/g (wrt 2 h PI control: Treatment Log₁₀ CFU/gthigh thigh) 5.04 Log₁₀CFU/g thigh) Early Infection Control [2 h PI]5.94 5.62 6 5.85 ± 0.2 NA Infection control [vehicle] 6.72 7.74 7.247.23 ± 0.51 −1.38 Ciprofloxacin [10 mg/kg, i.v. bolus] 3.74 3.94 3.523.73 ± 0.21* 2.12 Compound 2[3 mg/kg, i.v., 5.37 4.64 5.23 5.08 ±0.39^(#) 0.77 1 h infusion] Compound 2[10 mg/kg, i.v., 4.44 4.57 4.214.41 ± 0.18* 1.44 1 h infusion] Compound 2 [30 mg/kg, i.v., 2.66 2.63.24 2.83 ± 0.35* 3.02 1 h infusion]

TABLE 9 Efficacy of Compound 2 against K. pneumoniae [ATCC13883] in aNeutropenic Thigh Infection Model in Rat MEAN ± SD Mean Log 10 CFU/thigh(Log₁₀ CFU/g reduction (wrt 2 h PI control: Treatment Log₁₀ CFU/g thighthigh) 5.04 Log₁₀CFU/g thigh) Early Infection Control [2 h PI] 4.54 5.145.43 5.04 ± 0.45 Infection control [vehicle] 6.45 6.69 6.92 6.69 ± 0.24−1.65 Ciprofloxacin [10 mg/kg, i.v. bolus] 3.22 3.25 3.42 3.30 ± 0.11*1.74 Compound 2[3 mg/kg, i.v., 1 h infusion] 3.95 3.87 3.91 3.91 ± 0.04*1.13 Compound 2[10 mg/kg, i.v., 1 h 3.74 3.26 3.84 3.61 ± 0.31* 1.43infusion] Compound 2|[30 mg/kg, i.v., 1 h 2.48 2.29 2.92 2.56 ± 0.32*2.48 infusion]

Example 2 showed significant dose dependent bactericidal efficacy withrespect to 2 h Post Infection (PI) control at 3, 10 and 30 mg/kg, andthe efficacy was comparable to standard drug ciprofloxacin at similardose (10 mg/kg). *(P<0.05) Significantly different from Infectioncontrol 2 hr PI:#(P<0.05) Significantly different from Infection control10 hr PI.

In Vivo Efficacy in Rat Urinary Tract Infection (UTI) E. coli Model:

The purpose of this study is to assess the efficacy of Compound 2against E. coli [ATCC25922] following single dose intravenous infusiondoses of 3, 10 and 30 mg/kg in a Urinary Tract Infection Rat Model.

Procedure

Prior to the start of the infection process all animals were dividedinto different groups. All grouped cages of animals were carried to aprocedure room, close to a biological safety cabinet. All infectionswere conducted in a biological safety cabinet, with appropriatepersonnel protection. Animals were anaesthetized by intraperitonealinjection of ketamine & xylazine (60+10 mg/kg i.p.) cocktail. Once theanimals were in a sufficiently deep plane of anaesthesia as monitored bypedal reflex, the abdominal wall of each rat was shaved with electricclippers and the skin was cleansed with 10% povidine iodine. After a 1.5to 2 cm lower abdominal wall incision, the abdominal wall muscles wereseparated with blunt dissection. The urinary bladder was isolated andexposed, the urine inside the bladder was removed and 0.1 ml of sterilesaline or bacterial culture E. coli (approximately 1×108 CFU/animal) wasinjected into the bladder. After the replacement of the bladder to itsoriginal location, the abdominal muscles were approximated using sutureand the skin was closed. The wounds were cleansed using 10% povidineiodine.

The IV formulation vehicle used was 10% of L-ascorbic acid in freshMilliQ water (w/v) with pH adjusted to 4.0 with 1N Sodium hydroxidesolution (w/v), and the dose volume was 10 mL/kg. Meropenem was preparedin MilliQ water and the pH of solution was adjusted to 4.5 using HCl.Four hours post infection, animals were dosed intravenously, as singledoses (for test compounds), as a constant rate infusion, under Ketamine60 mg/kg IP+Xylazine 10 mg/kg IP anesthesia, at a dose volume of 10ml/kg, at the rate of 0.03 ml/min. The dose levels of the test compoundswere 3, 10 and 30 mg/kg. Meropenem was administered as a single bolusdose at a dose volume of 5 ml/kg.

All the animals were sacrificed at 24 h post infection, as specified inexperimental design, by an overdose of CO₂ in an appropriate exposurechamber. The group 1 animals were sacrificed at 4 h post infection.

The euthanized animals were dipped into 70% ethanol for surfacedecontamination. The organs were removed aseptically; the bladder wascut away near the urethra, and the kidneys were removed by bluntdissection to avoid bleeding. The bladder and each kidney separatelywere be homogenized in PBS. The CFU per milliliter homogenate ofbladder, & kidney were determined after 18 to 24 h of incubation at 37°C. The number of bacteria per organ was enumerated and the results ofthe study are presented in Table 9 and 10.

TABLE 10 Efficacy of Compound 2 against E. coli [ATCC25922] in UrinaryTract Infection Rat Model-Kidneys Mean Log₁₀CFU/g MEAN ± SD kidneyreduction (wrt 4 h Log₁₀ CFU/g Log₁₀ CFU/g (Log₁₀ CFU/g PI control: 4.53Treatment (Left Kidney) (Right Kidney) kidneys) Log₁₀CFU/g kidneys)Early Infection Control [4 h PI] 4.66 4.22 4.89 4.28 4.61 4.51 4.53 ±0.25 Infection control [vehicle 10 h PI] 5.29 5.32 5.11 5.18 5.24 5.485.27 ± 0.13 −0.74 Meropenem [30 mg/kg, i.v. bolus] 3.61 3.92 4.06 3.414.12 3.87 3.83 ± 0.27* 0.70 Compound 2 [3 mg/kg, i.v., 1 h infusion]5.39 5.17 5.24 4.68 4.90 5.39 5.13 ± 0.28^(#) −0.60 Compound 2 [10mg/kg, i.v., 1 h infusion] 4.12 3.78 4.46 4.11 3.65 3.61 3.95 ± 0.33*0.58 Compound 2 [30 mg/kg, i.v., 1 h infusion] 3.22 3.36 2.80 2.77 2.752.55 2.91 ± 0.31* 1.62 *(P < 0.05) significantly different fromInfection control 4 hr PI; ^(#)(P < 0.05) significantly different fromInfection control 24 hr PI.

TABLE 11 Efficacy of Compound 2 against E. coli [ATCC25922] in UrinaryTract Infection Rat Model-bladder MEAN ± SD Mean Log₁₀ CFU/ml Bladder(Log₁₀ CFU/ml reduction (wrt 4 h PI control: Treatment Log₁₀ CFU/mlBladder Bladder) 5.72 CFU/ml Bladder) Early Infection Control [4 h PI]5.53 6.26 5.38 5.72 ± 0.47 Infection control [vehicle 10 h PI] 7.43 7.527.13 7.36 ± 0.2 −1.64 Meropenem [30 mg/kg, i.v. bolus] 4.87 4.33 4.894.69 ± 0.32* 1.03 Compound 2 [3 mg/kg, i.v., 1 h infusion] 5.43 6.166.08 5.89 ± 0.4# −0.17 Compound 2 [10 mg/kg, i.v., 1 h infusion] 5.024.61 4.76  4.8 ± 0.2# 0.92 Compound 2 [30 mg/kg, i.v., 1 h infusion]4.19 3.90 3.58 3.89 ± 0.3* 1.83 *(P < 0.05) significantly different fromInfection control 4 hr PI; #(P < 0.05) significantly different fromInfection control 24 hr PI.

Compound 2 showed significant dose dependent bactericidal effect withrespect to 4 h PI control at 10 and 30 mg/kg and was bacteriostatic at 3mg/kg when compared to the 4 h PI control and the efficacy was betterthan standard drug meropenem at similar dose (30 mg/kg).

In Vivo Efficacy in Rat Lung P. aeruginosa Model:

The purpose of this study was to evaluate the efficacy of Compound 2against P. aeruginosa [ATCC27853], following single dose intravenousinfusion doses of 10, 30 and 100 mg/kg in a neutropenic lung infectionmodel in rats.

Procedure

Prior to the start of the infection process, all animals were dividedinto different groups. All grouped cages of animals were carried to aprocedure room, close to a biological safety cabinet. All infectionswere conducted in a biological safety cabinet, with appropriatepersonnel protection. Animals were placed into an induction chamber andanaesthesia was induced by exposing the animals to 3-5% Isoflurane in anoxygen flow set at approximately (˜) 1 liter per minute (LPM). Once theanimals were in a sufficiently deep plane of anaesthesia as monitored bypedal reflex, they were removed and infected (2). Infection wasinitiated by instilling 0.07 ml (containing ˜1×109 CFU/ml) of theinoculum; 35 μl into each nostril of the anesthetized animal using 100μl pipette (˜7×107 CFU/animal). A gentle mixing of inoculum between twoanimals was followed for uniform distribution.

The IV formulation vehicle used for Compound 2 was 10% of L-ascorbicacid in fresh MilliQ water (w/v) with pH adjusted to 4.0 with 1N Sodiumhydroxide solution (w/v), and the dose volume was 10 mL/kg. Meropenemwas formulated in saline. Four hours post infection, animals were dosedintravenously, as single doses, by infusion, under Ketamine 60 mg/kgIP+Xylazine 10 mg/kg IP anesthesia, at a dose volume of 10 ml/kg, at aconstant rate of 0.03 ml/min. The dose levels of the test Compound 2were 10, 30 and 100 mg/kg.

All the animals in groups were sacrificed at 24 h post infection, asspecified in experimental design, by an overdose of CO₂ in anappropriate exposure chamber. The group 1 animals were sacrificed at 4hrs post infection. The euthanized animals were dipped into 70% ethanolfor surface decontamination. Entire Lung was aseptically isolated,weighed and placed into 1 mL of sterile CSDB broth, and homogenized(Omni Tip (220 V hand held)). Serial ten-fold dilutions of the lungshomogenates were prepared in sterile CSD broth and 0.05 mL of fourdilutions for each tissue was plated onto CSDA agar plates. Bacterialcolonies were enumerated following overnight incubation at 37° C.Bacterial densities were estimated as Log₁₀ CFU/g lung. The Mean±SDLog₁₀ CFU/g lung was estimated in each group. Significant differencesbetween group means and control were analyzed by One-way ANOVA, followedby a Dunnett's multiple comparison test, using Graphpad Prism at 95%confidence levels. A P value of <0.05 was considered as significant andthe results of the study was presented in Table 10.

TABLE 12 Efficacy of Compound 2 against P. aeruginosa [ATCC27853] in aNeutropenic Lung Infection Model in Rat MEAN ± SD Mean Log 10 CFU/g lung(Log₁₀ CFU/g reduction (wrt 4 h PI control: Treatment Log₁₀ CFU/g LungLung) 6.52 Log₁₀CFU/g lung) Early Infection Control [4 h PI] 6.96 6.326.27 6.52 ± 0.38 NA Infection control [vehicle] 9.05 9.03 9.09 9.05 ±0.03 −2.53 Meropenem [30 mg/kg, i.v. bolus] 5.35 5.36 5.59 5.43 ± 0.14*1.09 Compound 2 [3 mg/kg, i.v., 1 h infusion] 7.99 8.02 8.26 8.09 ±0.14# −1.57 Compound 2 [10 mg/kg, i.v., 1 h infusion] 7.34 6.98 6.466.93 ± 0.44# −0.41 Compound 2 [30 mg/kg, i.v., 1 h infusion] 5.30 5.635.14 5.35 ± 0.25* 1.17 Compound 2 [100 mg/kg, i.v., 1 h infusion] 3.123.20 2.98  3.1 ± 0.12* 3.42 Data analysis: One-way Annova followed byDunnett's Multiple Comparison Test; *(P < 0.05) significantly differentfrom Infection control 4 hr PI. #(P < 0.05) significantly different fromInfection control 24 hr PI.

Compound 2 showed significant efficacy at 30 mg/kg and 100 mg/kg doseswith respect to early infection control and the efficacy was comparableto standard drug meropenem at similar dose (30 mg/kg).

Advantage

The above-mentioned implementation examples as described on this subjectmatter and its equivalent thereof have many advantages, including thosewhich are described.

The compounds of the present disclosure show high antibacterial activityagainst various pathogens including Gram-positive and Gram-negativebacteria through the inhibition of bacterial topoisomerase via a novelmechanism.

The compounds of the present disclosure demonstrate high degree ofselectivity against hERG channel (cardiac potassium channel) and may bedevoid of cardio toxicity in animal and human.

Representative exemplification of the present disclosure demonstrates ofdesirable pharmacokinetic profile in rat and efficacious in various ratinfection models thus confirming in vivo proof of principle in animalthrough inhibition of bacterial topoisomerase

Although the subject matter has been described in considerable detailwith reference to certain embodiments thereof, other embodiments arepossible. As such, the spirit and scope of the invention should not belimited to the description of the embodiments contained herein.

We claim:
 1. A compound of Formula I

or its stereoisomers, pharmaceutically acceptable salts, hydrates, solvates, tautomers, polymorphs, racemic mixtures, or optically active forms, thereof, wherein R₁ is selected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₃₋₆ cycloalkyl, C₁₋₆ alkylamino, C₁₋₆ aminoalkylene, or 4-7 membered saturated or unsaturated, carbocyclyl or heterocyclyl ring, wherein the heterocyclyl ring is optionally substituted with up to three heteroatoms independently selected from O, N or S, wherein C₁₋₆ alkyl, C₂₋₆ alkenyl, C₃₋₆ cycloalkyl, C₁₋₆ alkylamino, C₁₋₆ aminoalkylene, and 4-7 membered saturated or unsaturated carbocyclyl or heterocyclyl ring are optionally substituted with 1 to 3 groups independently selected from halogen, amino, hydroxyl, SO₃H, O—PO₃H₂, COOR₉, CONHR₉, SO₂NHR₉, methylsulfone, C₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₆ haloalkoxy, C₃₋₆ cycloalkyl, C₃₋₆ cycloalkylamino, C₃₋₆ aminocycloalkyl, C₃₋₆ cycloalkylhydroxy, C₁₋₆ alkylamino, or 3-7 membered saturated or unsaturated heterocyclyl ring optionally substituted with up to three heteroatoms independently selected from O, N or S; R₉ is selected from hydrogen, or C₁₋₆ alkyl; R₂ is selected from hydrogen, fluorine, chlorine, cyano, C₁₋₆ alkoxy, or hydroxyl; R₃ is selected from hydrogen, C₁₋₆ alkyl, fluorine, C₁₋₆ alkoxy, hydroxyl, or amino; X₁ is N or CR₄; R₄ is selected from hydrogen, halogen, cyano, C₁₋₆ alkoxy, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, or C₁₋₆ alkyl; X₂ is N or CR₅; R₅ is selected from hydrogen, halogen, cyano, C₁₋₆ alkoxy, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, or C₁₋₆ alkyl; X₃ is N or CR₆; and X₄ is CR₆ when dotted line (----) represents a bond; R₆ is selected from hydrogen, cyano, C₁₋₆ alkyl, C₁₋₆ alkylamino, C₁₋₆ alkoxy, C₁₋₆ haloalkoxy, or COOH; or X₃ is CH₂ or O; and X₄ is CH₂ when dotted line (----) represents no bond; n₁ is 0 to 2; Y₁, and Y₂ are independently selected from N or CR₇; R₇ is selected from hydrogen, halogen, cyano, C₁₋₆ alkoxy, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, or C₁₋₆ alkyl; Z₁ is selected from O, S, NH, or CH₂; and R₈ is selected from hydrogen, hydroxyl, C₁₋₆ alkyl, or fluorine.
 2. The compound as claimed in claim 1, or its stereoisomers, pharmaceutically acceptable salts, hydrates, solvates, tautomers, polymorphs, racemic mixtures, or optically active forms thereof, wherein R₁ is selected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₃₋₆ cycloalkyl, C₁₋₆ alkylamino, C₁₋₆ aminoalkylene, or 4-7 membered saturated or unsaturated carbocyclyl or heterocyclyl ring, wherein the heterocyclyl ring is optionally substituted with up to three heteroatoms independently selected from O, N or S, wherein C₁₋₆ alkyl, C₂₋₆ alkenyl, C₃₋₆ cycloalkyl, C₁₋₆ alkylamino, C₁₋₆ aminoalkylene, and 4-7 membered saturated or unsaturated carbocyclyl or heterocyclyl ring are optionally substituted with 1 to 3 groups independently selected from halogen, amino, hydroxyl, SO₃H, O—PO₃H₂, COOR₉, CONHR₉, SO₂NHR₉, methylsulfone, C₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₆ haloalkoxy, C₃₋₆ cycloalkyl, C₃₋₆ cycloalkylamino, C₃₋₆ aminocycloalkyl, C₃₋₆ cycloalkylhydroxy, C₁₋₆ alkylamino or 3-7 membered saturated or unsaturated heterocyclyl ring optionally substituted with up to three heteroatoms independently selected from O, N or S; R₉ is selected from hydrogen, or C₁₋₆ alkyl; R₂ is selected from hydrogen, fluorine, chlorine, C₁₋₄ alkoxy, cyano, or hydroxyl; R₃ is selected from hydrogen, fluorine, C₁₋₄ alkoxy, hydroxyl, or amino; X₁ is N or CR₄; R₄ is selected from hydrogen, halogen, cyano, C₁₋₄ alkoxy, C₁₋₄ haloalkyl, C₁₋₄ haloalkoxy, or C₁₋₄ alkyl; X₂ is N or CR₅; R₅ is selected from hydrogen, halogen, cyano, C₁₋₄ alkoxy, C₁₋₄ haloalkyl, C₁₋₄ haloalkoxy, or C₁₋₄ alkyl; X₃ is N or CR₆; and X₄ is CR₆ when dotted line (----) represents a bond; R₆ is selected from hydrogen, cyano, C₁₋₄ alkyl, C₁₋₄ alkylamino, C₁₋₄ alkoxy, C₁₋₄ haloalkoxy, and COOH; or X₃ is CH₂ or O; and X₄ is CH₂ when dotted line (----) represents no bond; n₁ is 0 to 2; Y₁, and Y₂ are independently selected from N or CR₇; R₇ is selected from hydrogen, halogen, cyano, C₁₋₄ alkoxy, C₁₋₄ haloalkyl, C₁₋₄ haloalkoxy, or C₁₋₄ alkyl; Z₁ is selected from O, S, NH, or CH₂; and R₈ is selected from hydrogen, hydroxyl, C₁₋₆ alkyl, or fluorine.
 3. The compound as claimed in claim 1, or its stereoisomers, pharmaceutically acceptable salts, hydrates, solvates, tautomers, polymorphs, racemic mixtures, or optically active forms thereof, wherein R₁ is selected from C₁₋₄ alkyl, C₃₋₄ cycloalkyl, C₁₋₄ alkylamino, or 4-7 membered saturated carbocyclyl or heterocyclyl ring, wherein the heterocyclyl ring is optionally substituted with up to three heteroatoms independently selected from O, N or S, wherein C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₃₋₄ cycloalkyl, C₁₋₄ alkylamino, and 4-7 membered saturated carbocyclyl or heterocyclyl ring are optionally substituted with 1 to 3 groups independently selected from halogen, amino, hydroxyl, O—PO₃H₂, C₁₋₄ alkyl, C₁₋₄ alkoxy, C₁₋₄ haloalkoxy, C₃₋₅ cycloalkyl, C₃₋₅ cycloalkylamino, C₃₋₅ aminocycloalkyl, C₃₋₆ cycloalkylhydroxy, C₁₋₄ alkylamino, or 3-7 membered saturated or unsaturated heterocyclyl ring optionally substituted with up to three heteroatoms independently selected from O, N or S; R₂ is selected from hydrogen, fluorine, C₁₋₂ alkoxy, cyano, or hydroxyl; R₃ is selected from hydrogen, fluorine, C₁₋₂ alkoxy, hydroxyl, or amino; X₁ is N or CR₄; R₄ is selected from hydrogen, halogen, cyano, C₁₋₂ alkoxy, C₁₋₂ haloalkyl, C₁₋₂ haloalkoxy, or C₁₋₂ alkyl; X₂ is N or CR₅; R₅ is selected from hydrogen, halogen, cyano, C₁₋₂ alkoxy, C₁₋₂ haloalkyl, C₁₋₂ haloalkoxy, or C₁₋₂ alkyl; X₃ is N or CR₆; and X₄ is CH when dotted line (----) represents a bond; R₆ is selected from hydrogen, cyano, C₁₋₂ alkyl, C₁₋₃ alkylamino, C₁₋₂ alkoxy, C₁₋₂ haloalkoxy, or COOH; or X₃ is CH₂ or O; and X₄ is CH₂ when dotted line (----) represents no bond; n₁ is 0 or 1; Y₁, and Y₂ are independently selected from N or CR₇; R₇ is selected from hydrogen, halogen, cyano, C₁₋₂ alkoxy, C₁₋₂ haloalkyl, C₁₋₂ haloalkoxy, or C₁₋₂ alkyl; Z₁ is selected from O, S, NH, or CH₂; and R₈ is selected from hydrogen, hydroxyl, C₁₋₆ alkyl, or fluorine.
 4. The compound as claimed in claim 1, or its stereoisomers, pharmaceutically acceptable salts, hydrates, solvates, tautomers, polymorphs, racemic mixtures, or optically active forms thereof, wherein R₁ is selected from CH₃, CH₂CH₃, CH(CH₃)₂, cyclopropyl, cyclobutyl, CH₂CF₃, CH₂CHFCH₃, CH₂CF₂CH₃, CH₂CH(OH)CH₃, CH₂CH₂OH, CH₂CH₂OCH₃, CH₂CH(OCH₃)CH₃, CH₂CH₂NH₂, CH₂CH₂NHCH₃, CH₂CH(NH₂)CH₃, CH₂CHFCH₂NH₂, CH₂CF₂CH₂NH₂, CH₂CH₂OPO₃H₂, CH₂C(CH₃)₂OH, CH₂C(CH₃)₂OPO₃H₂,

R₂ is selected from H, F, Cl, OCH₃, CN, or OH; R₃ is selected from H, F, OCH₃, OH, or NH₂; X₁ is N or CR₄; R₄ is selected from H, F, CN, OCH₃, or CH₃; X₂ is N or CR₅; R₅ is selected from H, F, CN, OCH₃, CF₃, OCF₃, or CH₃; X₃ is N or CR₆; and X₄ is CH when dotted line (----) represents a bond; R₆ is selected from H, CN, COOH, CH₂NH₂, CH(CH₃)NH₂, OCH₃, OCF₃, or CH₃; or X₃ is CH₂ or O; and X₄ is CH₂ when dotted line (----) represents no bond; n₁ is 0 or 1; Y₁, and Y₂ are independently selected from N or CR₇; R₇ is selected from H, F, CN, OCH₃, or CH₃; Z₁ is selected from O, S, NH, or CH₂; and R₈ is selected from H, OH, C₁₋₆ alkyl, or F.
 5. The compound as claimed in claim 1, or its stereoisomers, pharmaceutically acceptable salts, hydrates, solvates, tautomers, polymorphs, racemic mixtures, or optically active forms thereof, which is selected from the group consisting of:

(S)-6-(5-(((2-((5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridin-4-yl)oxy)ethyl)amino)methyl)-2-oxooxazolidin-3-yl)-2H-pyrido[3,2-b][1,4]oxazin-3(4H)-one (Compound 1),

(S)-6-(5-(((2-((7-fluoro-1-methyl-2-oxo-1,2-dihydroquinolin-8-yl)oxy)ethyl)amino)methyl)-2-oxooxazolidin-3-yl)-2H-pyrazino[2,3-b][1,4]oxazin-3(4H)-one (Compound 2),

(R)-6-(5-(((2-((7-fluoro-1-methyl-2-oxo-1,2-dihydroquinolin-8-yl)oxy)ethyl)amino)methyl)-2-oxooxazolidin-3-yl)-2H-pyrazino[2,3-b][1,4]oxazin-3(4H)-one (Compound 3),

6-((5S)-5-(((1-((7-fluoro-1-methyl-2-oxo-1,2-dihydroquinolin-8-yl)oxy)propan-2-yl)amino)methyl)-2-oxooxazolidin-3-yl)-2H-pyrazino [2,3-b] [1,4]oxazin-3(4H)-one (Compound 4),

(S)-6-(5-(((2-((7-fluoro-1,4-dimethyl-2-oxo-1,2-dihydroquinolin-8-yl)oxy)ethyl)amino)methyl)-2-oxooxazolidin-3-yl)-2H-pyrazino[2,3-b][1,4]oxazin-3(4H)-one (Compound 5),

(S)-6-(5-(((2-((3-chloro-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridin-4-yl)oxy)ethyl)amino)methyl)-2-oxooxazolidin-3-yl)-2H-pyrazino [2,3-b] [1,4]oxazin-3(4H)-one (Compound 6),

(S)-6-(5-(((2-((6-fluoro-4-methyl-3-oxo-3,4-dihydroquinoxalin-5-yl)oxy)ethyl)amino)methyl)-2-oxooxazolidin-3-yl)-2H-pyrazino[2,3-b][1,4]oxazin-3(4H)-one (Compound 7),

(R)-6-(5-(((2-((6-fluoro-4-methyl-3-oxo-3,4-dihydroquinoxalin-5-yl)oxy)ethyl)amino)methyl)-2-oxooxazolidin-3-yl)-2H-pyrazino[2,3-b][1,4]oxazin-3(4H)-one (Compound 8),

(S)-6-(5-(((2-((6-fluoro-2,4-dimethyl-3-oxo-3,4-dihydroquinoxalin-5-yl)oxy)ethyl)amino)methyl)-2-oxooxazolidin-3-yl)-2H-pyrazino [2,3-6] [1,4]oxazin-3(4H)-one (Compound 9), and

(S)-5-(((2-((6-fluoro-4-methyl-3-oxo-3,4-dihydroquinoxalin-5-yl)oxy)ethyl)amino)methyl)-3-(3-oxo-3,4-dihydro-2H-pyrazino[2,3-b][1,4]thiazin-6-yl)oxazolidin-2-one (Compound 10).
 6. A compound of Formula (B)

or its stereoisomers, pharmaceutically acceptable salts, hydrates, solvates, tautomers, polymorphs, racemic mixtures, or optically active forms thereof, wherein Y₁ is selected from N or CR₇; Y₂ is N; R₇ is selected from hydrogen, halogen, cyano, C₁₋₆ alkoxy, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, or C₁₋₆ alkyl; Z₁ is selected from O, S, NH, or CH₂; and R₈ is selected from hydrogen, hydroxyl, C₁₋₆ alkyl, or fluorine.
 7. The compound as claimed in claim 6, or its stereoisomers, pharmaceutically acceptable salts, hydrates, solvates, tautomers, polymorphs, racemic mixtures, or optically active forms thereof, which is selected from the group consisting of:

(S)-6-(5-(aminomethyl)-2-oxooxazolidin-3-yl)-2H-pyrazino[2,3-b][1,4]oxazin-3(4H)-one (Intermediate V)

(R)-6-(5-(aminomethyl)-2-oxooxazolidin-3-yl)-2H-pyrazino[2,3-b][1,4]oxazin-3(4H)-one (Intermediate VI)

(S)-5-(aminomethyl)-3-(3-oxo-3,4-dihydro-2H-pyrazino[2,3-b][1,4]thiazin-6-yl)oxazolidin-2-one (Intermediate VII).
 8. A process of preparation of compounds of Formula (B) as claimed in claim 6, or its stereoisomers, pharmaceutically acceptable salts, hydrates, solvates, tautomers, polymorphs, racemic mixtures, or optically active forms thereof, said process comprising: a) reacting a compound of Formula (C), and a compound of Formula (D) in the presence of at least one catalyst and at least one solvent to obtain a compound of Formula (E); b) reacting the compound of Formula (E) and at least one nitrogen compound to obtain a compound of Formula (F); and c) reducing the compound of Formula (F) to obtain a compound Formula (B).


9. The process as claimed in claim 8, wherein the at least one catalyst is selected from a group consisting of Pd containing catalyst, t-BuXPhos-Pd, Pd(OAc)₂, and combinations thereof; the at least one solvent is selected from the group consisting of THF, toluene, dioxane, and combinations thereof, the at least one nitrogen compound is NaN₃.
 10. The process as claimed in claim 8, wherein reducing the compound of Formula (F) to obtain a compound Formula (B) is carried out in the presence of reducing agent selected from triphenyl phosphine [(PH₃P)/THF—H₂O], or hydrogen and palladium carbon (H₂/Pd—C).
 11. A process of preparation of compounds of Formula I as claimed in claim 1, or its stereoisomers, pharmaceutically acceptable salts, hydrates, solvates, tautomers, polymorphs, racemic mixtures, or optically active forms thereof, said process comprising reacting a compound of Formula (A), and a compound of Formula (B)

in presence of at least one reducing agent, and an adsorbent to obtain the compounds of Formula I, wherein R₁ of Formula (A) is selected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₃₋₆ cycloalkyl, C₁₋₆ alkylamino, C₁₋₆ aminoalkylene, or 4-7 membered saturated or unsaturated carbocyclyl or heterocyclyl ring, wherein the heterocyclyl ring is optionally substituted with up to three heteroatoms independently selected from O, N or S, wherein C₁₋₆ alkyl, C₂₋₆ alkenyl, C₃₋₆ cycloalkyl, C₁₋₆ alkylamino, C₁₋₆ aminoalkylene, and 4-7 membered saturated or unsaturated carbocyclyl or heterocyclyl ring are optionally substituted with 1 to 3 groups independently selected from halogen, amino, hydroxyl, SO₃H, O—PO₃H₂, COOR₉, CONHR₉, SO₂NHR₉, methylsulfone, C₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₆ haloalkoxy, C₃₋₆ cycloalkyl, C₃₋₆ cycloalkylamino, C₃₋₆ cycloalkylhydroxy, C₃₋₆ aminocycloalkyl, C₁₋₆ alkylamino, or 3-7 membered saturated or unsaturated heterocyclyl ring optionally substituted with up to three heteroatoms independently selected from O, N or S; R₉ is selected from hydrogen, or C₁₋₆ alkyl; R₂ is selected from hydrogen, fluorine, chlorine, cyano, C₁₋₆ alkoxy, or hydroxyl; R₃ is selected from hydrogen, C₁₋₆ alkyl, fluorine, C₁₋₆ alkoxy, hydroxyl, or amino; X₁ is N or CR₄; R₄ is selected from hydrogen, halogen, cyano, C₁₋₆ alkoxy, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, or C₁₋₆ alkyl; X₂ is N or CR₅; R₅ is selected from hydrogen, halogen, cyano, C₁₋₆ alkoxy, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, or C₁₋₆ alkyl; X₃ is N or CR₆; and X₄ is CR₆ when dotted line (----) represents a bond; R₆ is selected from hydrogen, cyano, C₁₋₆ alkyl, C₁₋₆ alkylamino, C₁₋₆ alkoxy, C₁₋₆ haloalkoxy, or COOH; or X₃ is CH₂ or O; and X₄ is CH₂ when dotted line (----) represents no bond; and n₁ is 0 to 2; R₈ of Formula (B) is selected from hydrogen, hydroxyl, C₁₋₆ alkyl, or fluorine; Y₁, and Y₂ are independently selected from N or CR₇; R₇ is selected from hydrogen, halogen, cyano, C₁₋₆ alkoxy, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, or C₁₋₆ alkyl; Z₁ is selected from O, S, NH, or CH₂; and R₁ of Formula I is selected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₃₋₆ cycloalkyl, C₁₋₆ alkylamino, C₁₋₆ aminoalkylene, or 4-7 membered saturated or unsaturated, carbocyclyl or heterocyclyl ring, wherein the heterocyclyl ring is optionally substituted with up to three heteroatoms independently selected from O, N or S, wherein C₁₋₆ alkyl, C₂₋₆ alkenyl, C₃₋₆ cycloalkyl, C₁₋₆ alkylamino, C₁₋₆ aminoalkylene, and 4-7 membered saturated or unsaturated carbocyclyl or heterocyclyl ring are optionally substituted with 1 to 3 groups independently selected from halogen, amino, hydroxyl, SO₃H, O—PO₃H₂, COOR₉, CONHR₉, SO₂NHR₉, methylsulfone, C₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₆ haloalkoxy, C₃₋₆ cycloalkyl, C₃₋₆ cycloalkylamino, C₃₋₆ aminocycloalkyl, C₃₋₆ cycloalkylhydroxy, C₁₋₆ alkylamino, or 3-7 membered saturated or unsaturated heterocyclyl ring optionally substituted with up to three heteroatoms independently selected from O, N or S; R₉ is selected from hydrogen, or C₁₋₆ alkyl; R₂ is selected from hydrogen, fluorine, chlorine, cyano, C₁₋₆ alkoxy, or hydroxyl; R₃ is selected from hydrogen, C₁₋₆ alkyl, fluorine, C₁₋₆ alkoxy, hydroxyl, or amino; X₁ is N or CR₄; R₄ is selected from hydrogen, halogen, cyano, C₁₋₆ alkoxy, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, or C₁₋₆ alkyl; X₂ is N or CR₅; R₅ is selected from hydrogen, halogen, cyano, C₁₋₆ alkoxy, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, or C₁₋₆ alkyl; X₃ is N or CR₆; and X₄ is CR₆ when dotted line (----) represents a bond; R₆ is selected from hydrogen, cyano, C₁₋₆ alkyl, C₁₋₆ alkylamino, C₁₋₆ alkoxy, C₁₋₆ haloalkoxy, or COOH or X₃ is CH₂ or O; and X₄ is CH₂ when dotted line (----) represents no bond; n₁ is 0 to 2; Y₁, and Y₂ are independently selected from N or CR₇; R₇ is selected from hydrogen, halogen, cyano, C₁₋₆ alkoxy, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, or C₁₋₆ alkyl; Z₁ is selected from O, S, NH, or CH₂; and R₈ is selected from hydrogen, hydroxyl, C₁₋₆ alkyl, or fluorine.
 12. The process as claimed in claim 11, wherein the at least one reducing agent is selected from the group consisting of sodium borohydride, sodium cyano borohydride, sodium triacetoxy borohydride, and combinations thereof.
 13. The process as claimed in claim 11, wherein the adsorbent is selected from the group consisting of molecular sieves, silica gel, zeolites, anhydrous sodium sulphate, anhydrous magnesium sulphate, activated charcoal, and combinations thereof.
 14. A medicament comprising the compound as claimed in claim 1 or its stereoisomers, pharmaceutically acceptable salts, hydrates, solvates, tautomers, polymorphs, racemic mixtures, or optically active forms thereof.
 15. A method of treating a disease or condition in a patient wherein said disease or condition is caused by a microorganism selected from the group consisting of Gram-positive, and Gram-negative pathogen comprising administering to the patient the compound as claimed in claim 1 or its stereoisomers, pharmaceutically acceptable salts, hydrates, solvates, tautomers, polymorphs, racemic mixtures, or optically active forms thereof.
 16. A pharmaceutical composition comprising a compound of Formula I, as claimed in claim 1 or its stereoisomers, pharmaceutically acceptable salts, hydrates, solvates, tautomers, polymorphs, racemic mixtures, or optically active forms thereof together with a pharmaceutically acceptable carrier.
 17. A pharmaceutical composition comprising a compound of Formula I as claimed in claim 1 or its stereoisomers, pharmaceutically acceptable salts, hydrates, solvates, tautomers, polymorphs, racemic mixtures, or optically active forms thereof together with a pharmaceutically acceptable carrier, and in combination with at least one antibiotic.
 18. A method for the treatment of a bacterial infection in a subject comprising: administering to the subject an effective amount of the compound as claimed in claim
 1. 19. The method as claimed in claim 18, wherein the bacterial infection is caused by a Gram-positive or a Gram-negative pathogen.
 20. The method as claimed in claim 19, wherein the bacterial infection is caused by Escherichia coli, Pseudomonas aurigenosa, Klebsiella pneumoniae, Acinetobacter baumannii, Enterobacter cloacae, Staphylococcus aureus, Enterococcus faecalis Enterococcus faecium, Legionella pneumophila, Mycoplasma pneumonia, Acinetobacter haemolyticus, Acinetobacter junii, Acinetobacter lwoffi, Burkholderia cepacia, Chlamydophila pneumoniae, Clostridium difficili, Enterobacter aerogenes, Enterobacter cloacae, Moraxella catarrhalis, Neisseria gonorrhoeae, Neisseria meningitides, Proteus mirabilis, Proteus houseri, Citrobacter freundii, Citrobacter kosari, Citrobacter barakii, Seratia marcescens, Klebsiella oxytoca, Morganella morganii, Helicobacter pyroli, or Mycobacterium tuberculosis.
 21. A pharmaceutical composition comprising a compound of Formula (B) as claimed in claim 6 or its stereoisomers, pharmaceutically acceptable salts, hydrates, solvates, tautomers, polymorphs, racemic mixtures, or optically active forms thereof together with a pharmaceutically acceptable carrier.
 22. A pharmaceutical composition comprising a compound of Formula (B) as claimed in claim 6 or its stereoisomers, pharmaceutically acceptable salts, hydrates, solvates, tautomers, polymorphs, racemic mixtures, or optically active forms thereof together with a pharmaceutically acceptable carrier, and in combination with at least one antibiotic. 